- Over the last two decades, our multidisciplinary research is to investigate the unique physiology of the different me... moreOver the last two decades, our multidisciplinary research is to investigate the unique physiology of the different metabolic states of TB-causing bacteria to tackle antimicrobial drug resistance through validating novel therapeutic targets, from identifying hits to optimising novel leads and repurposing existing immune-modulatory drugs to cure tuberculosis and other mycobacterial infections. Specialisation: Microbiology, Molecular Biology(Over the last two decades, our multidisciplinary research is to investigate the unique physiology of the different metabolic states of TB-causing bacteria to tackle antimicrobial drug resistance through validating novel therapeutic targets, from identifying hits to optimising novel leads and repurposing existing immune-modulatory drugs to cure tuberculosis and other mycobacterial infections. Specialisation: Microbiology, Molecular Biology)edit
Amaryllidaceae is a significant source of bioactive phytochemicals with a strong propensity to develop new drugs. The genera Allium, Tulbaghia, Cyrtanthus and Crinum biosynthesize novel alkaloids and other phytochemicals with traditional... more
Amaryllidaceae is a significant source of bioactive phytochemicals with a strong propensity to develop new drugs. The genera Allium, Tulbaghia, Cyrtanthus and Crinum biosynthesize novel alkaloids and other phytochemicals with traditional and pharmacological uses. Amaryllidaceae biomolecules exhibit multiple pharmacological activities such as antioxidant, antimicrobial, and immunomodulatory effects. Traditionally, natural products from Amaryllidaceae are utilized to treat non-communicable and infectious human diseases. Galanthamine, a drug from this family, is clinically relevant in treating the neurocognitive disorder, Alzheimer’s disease, which underscores the importance of the Amaryllidaceae alkaloids. Although Amaryllidaceae provide a plethora of biologically active compounds, there is tardiness in their development into clinically pliable medicines. Other genera, including Cyrtanthus and Tulbaghia, have received little attention as potential sources of promising drug candidates....
Research Interests:
The bulbs of Allium species are a known source of antibacterial phytochemicals. Anti-infective, efflux pump and biofilm inhibitory activities of bulb extracts of selected Ghanaian shallots Allium cepa var aggregatum were evaluated using... more
The bulbs of Allium species are a known source of antibacterial phytochemicals. Anti-infective, efflux pump and biofilm inhibitory activities of bulb extracts of selected Ghanaian shallots Allium cepa var aggregatum were evaluated using the HT-SPOTi assay and other whole-cell phenotypic screening techniques to determine their possible mechanisms of action. Ethanol and aqueous extracts of white A. cepa inhibited the growth of Mycobacterium smegmatis mc2 155 and Escherichia coli, respectively. The majority of the Allium extracts significantly (p < 0.05) exhibited efflux pump inhibitory activity against all the acid-fast, Gram-positive and Gram-negative strains used. Hexane and chloroform extract of the pink A. cepa and the aqueous extract of the white A. cepa significantly inhibited M. smegmatis biofilm formation. For Pseudomonas aeruginosa, the inhibition was observed at 250 µg/mL for the aqueous extract (~77.34%) and 125 µg/mL for the hexane extract (~76.51%). The results suggest...
Research Interests:
*<p>UNAM: UDP-MurNAc; UMA: UDP-MurNAc-L-Ala; UMAG: UDP-MurNAc-L-Ala-D-Glu; UMT: UDP-MurNAc-L-Ala-γ-D-Glu-m-DAP.</p>¤<p><a... more
*<p>UNAM: UDP-MurNAc; UMA: UDP-MurNAc-L-Ala; UMAG: UDP-MurNAc-L-Ala-D-Glu; UMT: UDP-MurNAc-L-Ala-γ-D-Glu-m-DAP.</p>¤<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060143#pone.0060143-Basavannacharya2" target="_blank">[15]</a>.</p>#<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060143#pone.0060143-Liger1" target="_blank">[27]</a>.</p>§<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060143#pone.0060143-PratvielSosa1" target="_blank">[67]</a>.</p>¥<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060143#pone.0060143-Duncan1" target="_blank">[32]</a>.</p
Research Interests:
Arylamine N-acetyltransferase (NAT) was first identified in humans for its role in metabolising the anti-tubercular drug isoniazid. Later functional NAT proteins were identified in bacteria including Mycobacterium tuberculosis where they... more
Arylamine N-acetyltransferase (NAT) was first identified in humans for its role in metabolising the anti-tubercular drug isoniazid. Later functional NAT proteins were identified in bacteria including Mycobacterium tuberculosis where they were found to N-acetylate a range of arylamines, hydrazines and hydralazines both in vitro and in vivo. From gene deletion and genomic studies in mycobacteria, it became clear that NAT in Mycobacterium bovis Bacillus Calmette–Guérin (BCG) had an endogenous role in cell-wall metabolism, cholesterol degradation and the nat gene was part of an essential gene cluster for intra-cellular survival of the pathogen M. tuberculosis; this has paved the way for validation of NAT and other proteins encoded in the gene cluster as novel therapeutic targets for anti-tubercular drug design and discovery. This chapter reviews the genomic organisation of the nat gene and the function of the NAT protein in mycobacteria, including the location of the nat gene in the genome. The role of nat and its neighbouring genes, their endogenous substrates and the regulation of their expression in fast-growing environmental and slow-growing pathogenic intra-cellular mycobacteria is also covered
Research Interests:
Fast-growing, non-infectious and intracellularly surviving drug-
The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has reinforced the need for the development of new anti-TB drugs. The first line drug isoniazid inhibits InhA. This is a prodrug requiring... more
The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has reinforced the need for the development of new anti-TB drugs. The first line drug isoniazid inhibits InhA. This is a prodrug requiring activation by the enzyme KatG. Mutations in KatG have largely contributed to clinical isoniazid resistance. We aimed to design new ‘direct’ InhA inhibitors that obviate the need for activation by KatG, circumventing pre-existing resistance. In silico molecular modelling was used as part of a rational structure-based drug-design approach involving inspection of protein crystal structures of InhA:inhibitor complexes, including the broad spectrum antibiotic triclosan (TCS). One crystal structure exhibited the unusual presence of two triclosan molecules within the Mycobacterium tuberculosis InhA binding site. This became the basis of a strategy for the synthesis of novel inhibitors. A series of new, flexible ligands were designed and synthesised, expandi...
Research Interests:
Research Interests:
Research Interests: Biochemistry, Microbiology, Medical Microbiology, Biology, Enzyme Inhibitors, and 12 moreMedicine, Mycobacterium tuberculosis, BCS, Antimicrobial chemotherapy, Enzyme, Oxford university, Microbial Sensitivity Tests, DNA ligase, Peptidoglycan, Pharmacophore, 4-Tetrahydroisoquinolines, and Pharmacology and pharmaceutical sciences
New therapies are required against Mycobacterium tuberculosis and its cell wall peptidoglycan biosynthesis is a potential therapeutic target. UDP-MurNAc-tripeptide ligase (MurE) is a member of the ATP-dependent ligase family, which... more
New therapies are required against Mycobacterium tuberculosis and its cell wall peptidoglycan biosynthesis is a potential therapeutic target. UDP-MurNAc-tripeptide ligase (MurE) is a member of the ATP-dependent ligase family, which incorporate amino acids including meso-diaminopimelic acid (m-DAP) into peptidoglycan during synthesis in a species-specific manner. In the present study, we have cloned, over-expressed, and characterised MurE from M. tuberculosis (Mtb-MurE). The crystal structure has been determined at 3.0A resolution in the presence of the substrate UDP-MurNAc-l-Ala-d-Glu (UAG). The activity of the enzyme was measured through estimating inorganic phosphate released in a non-radioactive high-throughput colourimetric assay. UDP-MurNAc-l-Ala-d-Glu-m-DAP (UMT) formation coupled to inorganic phosphate release was confirmed by HPLC and mass spectrometric analyses. Kinetic constants were determined for a range of natural substrates using optimised conditions. From our findings, it is evident that Mtb-MurE is highly specific in adding m-DAP to UDP-MurNAc-dipeptide and ATP-hydrolysis is an absolute requirement for its activity.
Research Interests:
Research Interests: Microbiology, Colorimetry, Colombia, Medical Microbiology, Biology, and 15 moreEnzyme Inhibitors, Medicine, Biological Sciences, Humans, Mycobacterium tuberculosis, Escherichia coli, Natural Product, Bacteria, Antimicrobial chemotherapy, Microbial Sensitivity Tests, Growth Inhibition, Microbial Viability, Mycobacterium bovis, Pharmacology and pharmaceutical sciences, and Biological products(Enzyme Inhibitors, Medicine, Biological Sciences, Humans, Mycobacterium tuberculosis, Escherichia coli, Natural Product, Bacteria, Antimicrobial chemotherapy, Microbial Sensitivity Tests, Growth Inhibition, Microbial Viability, Mycobacterium bovis, Pharmacology and pharmaceutical sciences, and Biological products)
(Enzyme Inhibitors, Medicine, Biological Sciences, Humans, Mycobacterium tuberculosis, Escherichia coli, Natural Product, Bacteria, Antimicrobial chemotherapy, Microbial Sensitivity Tests, Growth Inhibition, Microbial Viability, Mycobacterium bovis, Pharmacology and pharmaceutical sciences, and Biological products)
Research Interests: Chemistry, Enzyme Inhibitors, Medicine, Multidisciplinary, Animals, and 11 moreNat, High Pressure Liquid Chromatography, Arylamine N-acetyltransferase, Cattle, Substrate Specificity, Methotrexate, Acetylation, Molecular weight, Biochemistry and cell biology, p-aminobenzoic acid, and Medical biochemistry and metabolomics
Research Interests: Microbiology, Medical Microbiology, Biology, Macrophages, Medicine, and 12 moreCell line, Tuberculosis, Mycobacterium tuberculosis, Mycobacterium, Mice, High throughput screening, Animals, BCS, Antimicrobial chemotherapy, Microbial Sensitivity Tests, Intracellular, and Pharmacology and pharmaceutical sciences
Research Interests:
The authors wish to make the following corrections to this paper [...].
Research Interests:
Objectives: The aim of this study was to comprehensively evaluate the antibacterial activity and MurE inhibition of a set of N-methyl-2-alkenyl-4-quinolones found to inhibit the growth of fast-growing mycobacteria. Methods: Using the spot... more
Objectives: The aim of this study was to comprehensively evaluate the antibacterial activity and MurE inhibition of a set of N-methyl-2-alkenyl-4-quinolones found to inhibit the growth of fast-growing mycobacteria. Methods: Using the spot culture growth inhibition assay, MICs were determined for Mycobacterium tuberculosis H37Rv, Mycobacterium bovis BCG and Mycobacterium smegmatis mc 2155. MICs were determined for Mycobac-terium fortuitum, Mycobacterium phlei, methicillin-resistant Staphylococcus aureus, Escherichia coli and Pseudo-monas aeruginosa using microplate dilution assays. Inhibition of M. tuberculosis MurE ligase activity was determined both by colorimetric and HPLC methods. Computational modelling and binding prediction of the quinolones in the MurE structure was performed using Glide. Kinetic experiments were conducted for under-standing possible competitive relations of the quinolones with the endogenous substrates of MurE ligase.
Research Interests: Microbiology, Molecular Dynamics Simulation, Medical Microbiology, Humans, Escherichia coli, and 11 moreMycobacterium, Staphylococcus aureus, Antimicrobial chemotherapy, Quinolones, Pseudomonas aeruginosa, Anti-Bacterial Agents, Microbial Sensitivity Tests, Pseudomonas Aeruginosa, Cell Wall, Protein Binding, and Pharmacology and pharmaceutical sciences
ATP-dependent Mur ligases (Mur synthetases) play essential roles in the biosynthesis of cell wall peptidoglycan (PG) as they catalyze the ligation of key amino acid residues to the stem peptide at the expense of ATP hydrolysis, thus... more
ATP-dependent Mur ligases (Mur synthetases) play essential roles in the biosynthesis of cell wall peptidoglycan (PG) as they catalyze the ligation of key amino acid residues to the stem peptide at the expense of ATP hydrolysis, thus representing potential targets for antibacterial drug discovery. In this study we characterized the division/cell wall (dcw) operon and identified a promoter driving the co-transcription of mur synthetases along with key cell division genes such as ftsQ and ftsW. Furthermore, we have extended our previous investigations of MurE to MurC, MurD and MurF synthetases from Mycobacterium tuberculosis. Functional analyses of the pure recombinant enzymes revealed that the presence of divalent cations is an absolute requirement for their activities. We also observed that higher concentrations of ATP and UDP-sugar substrates were inhibitory for the activities of all Mur synthetases suggesting stringent control of the cytoplasmic steps of the peptidoglycan biosynthe...
Research Interests:
Tuberculosis (TB) is still a leading cause of death worldwide. Treatments remain unsatisfactory due to an incomplete understanding of the underlying host–pathogen interactions during infection. In the present study, weighted gene... more
Tuberculosis (TB) is still a leading cause of death worldwide. Treatments remain unsatisfactory due to an incomplete understanding of the underlying host–pathogen interactions during infection. In the present study, weighted gene co-expression network analysis (WGCNA) was conducted to identify key macrophage modules and hub genes associated with mycobacterial infection. WGCNA was performed combining our own transcriptomic results using Mycobacterium aurum-infected human monocytic macrophages (THP1) with publicly accessible datasets obtained from three types of macrophages infected with seven different mycobacterial strains in various one-to-one combinations. A hierarchical clustering tree of 11,533 genes was built from 198 samples, and 47 distinct modules were revealed. We identified a module, consisting of 226 genes, which represented the common response of host macrophages to different mycobacterial infections that showed significant enrichment in innate immune stimulation, bacter...
Research Interests:
Research Interests:
Background The rise of antimicrobial drug resistance in Mycobacterium tuberculosis coupled with the shortage of new antibiotics has elevated TB to a major global health priority. Repurposing drugs developed or used for other conditions... more
Background The rise of antimicrobial drug resistance in Mycobacterium tuberculosis coupled with the shortage of new antibiotics has elevated TB to a major global health priority. Repurposing drugs developed or used for other conditions has gained special attention in the current scenario of accelerated drug development for several global infectious diseases. In a similar effort, previous studies revealed that carprofen, a non-steroidal anti-inflammatory drug, selectively inhibited the growth of replicating, non-replicating and MDR clinical isolates of M. tuberculosis. Objectives We aimed to reveal the whole-cell phenotypic and transcriptomic effects of carprofen in mycobacteria. Methods Integrative molecular and microbiological approaches such as resazurin microtitre plate assay, high-throughput spot-culture growth inhibition assay, whole-cell efflux inhibition, biofilm inhibition and microarray analyses were performed. Analogues of carprofen were also synthesized and assessed for t...
Research Interests:
The genes encoding ABC transporters occupy 2.5% of the genome of Mycobacterium tuberculosis . However, none of these putative ABC transporters has been characterized so far. We describe the development of expression systems for... more
The genes encoding ABC transporters occupy 2.5% of the genome of Mycobacterium tuberculosis . However, none of these putative ABC transporters has been characterized so far. We describe the development of expression systems for simultaneous expression of the ATP binding protein DrrA and the membrane integral protein DrrB which together behave as a functional doxorubicin efflux pump. Doxorubicin uptake in Escherichia coli or Mycobacterium smegmatis expressing DrrAB was inhibited by reserpine, an inhibitor of ABC transporters. The localization of DrrA to the membrane depended on the simultaneous expression of DrrB. ATP binding was positively regulated by doxorubicin and daunorubicin. At the same time, DrrB appeared to be sensitive to proteolysis when expressed alone in the absence of DrrA. Simultaneous expression of the two polypeptides was essential in order to obtain a functional doxorubicin efflux pump. Expression of DrrAB in E. coli conferred 8-fold increased resistance to ethidiu...
Research Interests: Biological Sciences, Mycobacterium tuberculosis, Escherichia coli, Drug Resistance, Biochemical, and 14 moreLipid metabolism, CHEMICAL SCIENCES, Molecular cloning, Doxorubicin, Reserpine, Amino Acid Sequence, Base Sequence, DNA binding proteins, Verapamil, Adenosine Triphosphate, Calcium Channel Blockers, Molecular Sequence Data, Daunorubicin, and Medical and Health Sciences
The ascent of antimicrobial obstruction is prompting always untreatable ailment. Intracellularly enduring bacterial pathogens have endogenous apparatus to dodge have protections just as anti-microbial treatment. Medication efflux and... more
The ascent of antimicrobial obstruction is prompting always untreatable ailment. Intracellularly enduring bacterial pathogens have endogenous apparatus to dodge have protections just as anti-microbial treatment. Medication efflux and development of biofilms are the two key crucial systems of inherent obstruction which render numerous anti-microbials inadequate against them. Mycobacterium tuberculosis has extraordinary multitranquilize transporter protein edifices that permit the pathogen to take up supplements for endurance, while permitting it to expel malicious ones so as the flagging atoms for majority detecting prompting biofilm arrangement. Our work has demonstrated that the NonSteroidal Anti-Inflammatory Drugs (NSAIDs) have hostile to bacterial activity against Mycobacterium tuberculosis. The most strong NSAID up until this point, at subinhibitory fixations, repressed entire cell efflux siphons movement at standard with/better than powerful efflux siphon inhibitors, for exampl...
Objectives Identification and validation of novel therapeutic targets is imperative to tackle the rise of drug resistance in tuberculosis. An essential Mur ligase-like gene (Rv3712), expected to be involved in cell-wall peptidoglycan (PG)... more
Objectives Identification and validation of novel therapeutic targets is imperative to tackle the rise of drug resistance in tuberculosis. An essential Mur ligase-like gene (Rv3712), expected to be involved in cell-wall peptidoglycan (PG) biogenesis and conserved across mycobacteria, including the genetically depleted Mycobacterium leprae, was the primary focus of this study. Methods Biochemical analysis of Rv3712 was performed using inorganic phosphate release assays. The operon structure was identified using reverse-transcriptase PCR and a transcription/translation fusion vector. In vivo mycobacterial protein fragment complementation assays helped generate the interactome. Results Rv3712 was found to be an ATPase. Characterization of its operon revealed a mycobacteria-specific promoter driving the co-transcription of Rv3712 and Rv3713. The two gene products were found to interact with each other in vivo. Sequence-based functional assignments reveal that Rv3712 and Rv3713 are likel...
Tuberculosis (TB) is a highly contagious disease caused by Mycobacterium tuberculosis (Mtb) and is the major cause of morbidity and mortality across the globe. The clinical outcome of TB infection and susceptibility varies among... more
Tuberculosis (TB) is a highly contagious disease caused by Mycobacterium tuberculosis (Mtb) and is the major cause of morbidity and mortality across the globe. The clinical outcome of TB infection and susceptibility varies among individuals and even among different populations, contributed by host genetic factors such as polymorphism in the human leukocyte antigen (HLA) alleles as well as in cytokine genes, nutritional differences between populations, immunometabolism, and other environmental factors. Till now, BCG is the only vaccine available to prevent TB but the protection rendered by BCG against pulmonary TB is not uniform. To deliver a vaccine which can give consistent protection against TB is a great challenge with rising burden of drug-resistant TB. Thus, expectations are quite high with new generation vaccines that will improve the efficiency of BCG without showing any discordance for all forms of TB, effective for individual of all ages in all parts of the world. In order to enhance or improve the efficacy of BCG, different strategies are being implemented by considering the immunogenicity of various Mtb virulence factors as well as of the recombinant strains, co-administration with adjuvants and use of appropriate vehicle for delivery. This chapter discusses several such pre-clinical attempts to boost BCG with subunit vaccines tested in murine models and also highlights various recombinant TB vaccines undergoing clinical trials. Promising candidates include new generation of live recombinant BCG (rBCG) vaccines, VPM1002, which are deleted in one or two virulence genes. They encode for the mycobacteria-infected macrophage-inhibitor proteins of host macrophage apoptosis and autophagy, key events in killing and eradication of Mtb. These vaccines are rBCG- ΔureC::hly HMR, and rBCG-ΔureC::hly ΔnuoG. The former vaccine has passed phase IIb in clinical trials involving South African infants and adults. Thus, with an aim of elimination of TB by 2050, all these cumulative efforts to develop a better TB vaccine possibly is new hope for positive outcomes.
Research Interests:
With antimicrobial resistance creating a major public health crisis, the designing of novel antimicrobial compounds that effectively combat bacterial infection is becoming increasingly critical. Interdisciplinary approaches integrate the... more
With antimicrobial resistance creating a major public health crisis, the designing of novel antimicrobial compounds that effectively combat bacterial infection is becoming increasingly critical. Interdisciplinary approaches integrate the best features of whole-cell phenotypic evaluation to validate novel therapeutic targets and discover new leads to combat antimicrobial resistance. In this project, whole-cell phenotypic evaluation such as testing inhibitors on bacterial growth, viability, efflux pump, biofilm formation and their interaction with other drugs were performed on a panel of Gram-positive, Gram-negative and acid-fast group of bacterial species. This enabled additional antimicrobial activities of compounds belonging to the flavonoid family including ketones, chalcones and stilbenes, to be identified. Flavonoids have received renewed attention in literature over the past decade, and a variety of beneficial effects of these compounds have been illuminated, including anti-cancer, anti-inflammatory, anti-tumour as well as anti-fungal and anti-bacterial. However, their mechanisms of action are yet to be identified. In this paper, we found that the compounds belonging to the flavonoid family exerted a range of anti-infective properties being identified as novel efflux pump inhibitors, whilst offering the opportunity to be used in combination therapy. The compound 2-phenylacetophenone displayed broad-spectrum efflux pump inhibition activity, whilst trans-chalcone, displayed potent activity against Gram-negative and mycobacterial efflux pumps causing inhibition higher than known potent efflux pump inhibitors, verapamil and chlorpromazine. Drug-drug interaction studies also highlighted that 2-phenylacetophenone not only has the potential to work additively with known antibacterial agents that affect the cell-wall and DNA replication but also trans-chalcone has the potential to work synergistically with anti-tubercular agents. Overall, this paper shows how whole-cell phenotypic analysis allows for the discovery of new antimicrobial agents and their consequent mode of action whilst offering the opportunity for compounds to be repurposed, in order to contribute in the fight against antimicrobial resistance.
5‐Substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido[2,3‐d]pyrimidin‐4(3H)‐one derivatives were synthesized and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus as... more
5‐Substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido[2,3‐d]pyrimidin‐4(3H)‐one derivatives were synthesized and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus as well as a human monocyte‐derived macrophage (THP‐1), and murine macrophage (RAW 264.7) cell lines to assess their antibacterial and cytotoxic potential, respectively. The compounds showed activity in the range of 1.95–125 µg/ml against M. tuberculosis but showed no activity against M. aurum, E. coli, and S. aureus, indicating selectivity towards slow‐growing mycobacterial pathogens. The compounds exhibited very low to no cytotoxicity up to 500 µg/ml concentration against eukaryotic cell lines. The most potent molecule, 2l, showed a minimum inhibitory concentration of 1.95 µg/ml against M. tuberculosis H37Rv and a selectivity index of >250 against both the eukaryotic cell lines. Furthermore, 2l showed moderate inhibition of whole‐cell mycobacterial drug‐efflux pumps when compared to verapamil, a known potent inhibitor of efflux pumps. Thus, derivative 2l was identified as an antituberculosis hit molecule, which could be used to yield more potent lead molecules.
Research Interests:
Tuberculosis (TB), caused by the intracellular pathogen Mycobacterium tuberculosis, remains one of the leading causes of mortality across the world. There is an urgent requirement to build a robust arsenal of effective antimicrobials,... more
Tuberculosis (TB), caused by the intracellular pathogen Mycobacterium tuberculosis, remains one of the leading causes of mortality across the world. There is an urgent requirement to build a robust arsenal of effective antimicrobials, targeting novel molecular mechanisms to overcome the challenges posed by the increase of antibiotic resistance in TB. Mycobacterium tuberculosis has a unique cell envelope structure and composition, containing a peptidoglycan layer that is essential for maintaining cellular integrity and for virulence. The enzymes involved in the biosynthesis, degradation, remodelling and recycling of peptidoglycan have resurfaced as attractive targets for anti-infective drug discovery. Here, we review the importance of peptidoglycan, including the structure, function and regulation of key enzymes involved in its metabolism. We also discuss known inhibitors of ATP-dependent Mur ligases, and discuss the potential for the development of pan-enzyme inhibitors targeting mu...
Research Interests:
Research Interests:
Research Interests:
Disulfides from Allium stipitatum, commonly known as Persian shallot, were previously reported to possess antibacterial properties. Analogues of these compounds, produced by S-methylthiolation of appropriate thiols using S-methyl... more
Disulfides from Allium stipitatum, commonly known as Persian shallot, were previously reported to possess antibacterial properties. Analogues of these compounds, produced by S-methylthiolation of appropriate thiols using S-methyl methanethiosulfonate, exhibited antimicrobial activity, with one compound inhibiting the growth of Mycobacterium tuberculosis at 17 µM (4 mg L-1) and other compounds inhibiting Escherichia coli and multi-drug-resistant (MDR) Staphylococcus aureus at concentrations ranging between 32-138 µM (8-32 mg L-1). These compounds also displayed moderate inhibitory effects on Klebsiella and Proteus species. Whole-cell phenotypic bioassays such as the spot-culture growth inhibition assay (SPOTi), drug efflux inhibition, biofilm inhibition and cytotoxicity assays were used to evaluate these compounds. Of particular note was their ability to inhibit mycobacterial drug efflux and biofilm formation, while maintaining a high selectivity towards M. tuberculosis H37Rv. These ...
Research Interests: Pharmacology, Biofilms, Drug Discovery, Tuberculosis and Infectious Disease, Antimicrobial drug resistance, and 10 moreMycobacterium tuberculosis, Escherichia coli, Klebsiella, Staphylococcus aureus, Extraction of Antimicrobial Activety of Medicinal Plants Against Some Disease Causing Microorganism, Plant extracts, Microbial Sensitivity Tests, Natural Products and drug discovery, Proteus, and Allium
Research Interests:
Background Traditional antibiotics are increasingly suffering from the emergence of multidrug resistance amongst pathogenic bacteria leading to a range of novel approaches to control microbial infections being investigated as potential... more
Background Traditional antibiotics are increasingly suffering from the emergence of multidrug resistance amongst pathogenic bacteria leading to a range of novel approaches to control microbial infections being investigated as potential alternative treatments. One plausible antimicrobial alternative could be the combination of conventional antimicrobial agents/antibiotics with small molecules which block multidrug efflux systems known as efflux pump inhibitors. Bioassay-driven purification and structural determination of compounds ...
Research Interests: Engineering, Chemistry, Biofilms, Biology, Antibiotic Susceptibility Testing, and 15 moreHumans, Gram Positive, Animals, Antimicrobial activity, Artemisia, Berberine, Gram Positive Bacteria, Liquid Chromatography, Efflux Pumps, Chlorogenic Acid, Hemolysis, Artemisia Absinthium, Efflux pump inhibitors, Drug synergism, and Antimicrobial agent
Research Interests:
The present study aimed to screen plants for bioactive compounds with potential antibacterial activities. In our efforts to evaluate plants from Borneo, we isolated and elucidated the structures of four natural products from the bioactive... more
The present study aimed to screen plants for bioactive compounds with potential antibacterial activities. In our efforts to evaluate plants from Borneo, we isolated and elucidated the structures of four natural products from the bioactive fraction of a chloroform extract of Goniothalamus longistipetes using various chromatographic and spectroscopic techniques. The bioactive compounds were identified as a known styryllactone, (+)-altholactone ((2S,3R,3aS,7aS)-3-hydroxy-2-phenyl-2,3,3a,7a-tetrahydrobenzo-5(4H)-5-one) (1), a new styryllactone, (2S,3R,3aS,7aS)-3-hydroxy-2-phenyl-2,3,3a,7a-tetrahydrobenzo-5(4H)-5-one) (2) as well as a new alkaloid, 2,6-dimethoxyisonicotinaldehyde (3) and a new alkenyl-5-hydroxyl-phenyl benzoic acid (4). 1 and 4 showed broad-spectrum anti-bacterial activities against Gram-positive and Gram-negative bacteria as well as acid-fast model selected for this study. Compound 2 only demonstrated activities against Gram-positive bacteria whilst 3 displayed selectiv...
Research Interests:
In this study, the inhibitory potential of 3-(5-nitrofuran-2-yl)prop-2-en-1-one derivatives was evaluated against a panel of bacteria, as well as mammalian cell lines to determine their therapeutic index. In addition, we investigated the... more
In this study, the inhibitory potential of 3-(5-nitrofuran-2-yl)prop-2-en-1-one derivatives was evaluated against a panel of bacteria, as well as mammalian cell lines to determine their therapeutic index. In addition, we investigated the mechanism of antibiotic action of the derivatives to identify their therapeutic target. We discovered compound 2 to be an extremely potent inhibitor of Mycobacterium tuberculosis H37Rv growth (MIC: 0.031 mg/L) in vitro, performing better than the currently used first-line antituberculosis drugs such as isoniazid, rifampicin, ethambutol, and pretomanid in vitro. Furthermore, compound 3 was equipotent to pretomanid against a multidrug-resistant M. tuberculosis clinical isolate. The derivatives were selective and bactericidal towards slow-growing mycobacteria. They showed low cytotoxicity towards murine RAW 264.7 and human THP-1 cell lines, with high selectivity indices. Compound 1 effectively eliminated the intracellular mycobacteria in a mycobacteria...
Research Interests:
Therapeutic treatment options for opportunistic non-tuberculous mycobacterial (NTM) infection and/or serious mycobacterial infections such as tuberculosis (TB) and leprosy are limited due to the spread of antimicrobial resistance... more
Therapeutic treatment options for opportunistic non-tuberculous mycobacterial (NTM) infection and/or serious mycobacterial infections such as tuberculosis (TB) and leprosy are limited due to the spread of antimicrobial resistance mechanism. Plant-derived natural compounds as prospective efflux pump inhibitors may present a promising adjunct to conventional chemotherapy by enhancing mycobacterial susceptibility to antibiotics. This study served to evaluate the antimicrobial and resistance-modifying profile of a range of plant-derived flavonoids against the mycobacterial model strains: M. smegmatis, M. aurum, and M. bovis BCG. The minimum inhibitory concentrations (MICs) of the compounds against the mycobacterial strains were determined using both agar dilution and broth dilution assays, while their efflux inhibitory activity was investigated via an ethidium bromide-based fluorometric assay. All compounds were screened for their synergistic effects with ethidium bromide (EtBr) and rif...
Research Interests:
Tuberculosis (TB) continues to be a devastating infectious disease and remerges as a global health emergency due to an alarming rise of antimicrobial resistance to its treatment. Despite of the serious effort that has been applied to... more
Tuberculosis (TB) continues to be a devastating infectious disease and remerges as a global health emergency due to an alarming rise of antimicrobial resistance to its treatment. Despite of the serious effort that has been applied to develop effective antitubercular chemotherapies, the potential of antimicrobial peptides (AMPs) remains underexploited. A large amount of literature is now accessible on the AMP mechanisms of action against a diversity of pathogens; nevertheless, research on their activity on mycobacteria is still scarce. In particular, there is an urgent need to integrate all available interdisciplinary strategies to eradicate extensively drug-resistantstrains. In this context, we should not underestimate our endogenous antimicrobial proteins and peptides as ancient players of the human host defense system. We are confident that novel antibiotics based on human AMPs displaying a rapid and multifaceted mechanism, with reduced toxicity, should significantly contribute to...
Tuberculosis (TB) is a dreadful bacterial disease, infecting millions of human and cattle every year worldwide. More than 50 years after its discovery, ethambutol continues to be an effective part of the World Health Organization's... more
Tuberculosis (TB) is a dreadful bacterial disease, infecting millions of human and cattle every year worldwide. More than 50 years after its discovery, ethambutol continues to be an effective part of the World Health Organization's recommended frontline chemotherapy against TB. However, the lengthy treatment regimens consisting of a cocktail of antibiotics affect patient compliance. There is an urgent need to improve the current therapy so as to reduce treatment duration and dosing frequency. In this study, we have designed a novel anti-TB multifunctional formulation by fabricating graphene oxide with iron oxide magnetite nanoparticles serving as a nano-carrier on to which ethambutol was successfully loaded. The designed nanoformulation was characterised using various analytical techniques. The release of ethambutol from anti-TB multifunctional nanoparticles formulation was found to be sustained over a significantly longer period of time in phosphate buffer saline solution at tw...
Research Interests:
Tuberculosis (TB) is a bacterial disease responsible for millions of infections and preventable deaths each year. Its treatment is complicated by patients' noncompliance due to dosing frequency, lengthy treatment, and adverse side... more
Tuberculosis (TB) is a bacterial disease responsible for millions of infections and preventable deaths each year. Its treatment is complicated by patients' noncompliance due to dosing frequency, lengthy treatment, and adverse side effects associated with current chemotherapy. However, no modifications to the half-a-century old standard chemotherapy have been made based on a nanoformulation strategy to improve pharmacokinetic efficacy. In this study, we have designed a new nanodelivery formulation, using graphene oxide as the nanocarrier, loaded with the anti-TB antibiotic, ethambutol. The designed formulation was characterized using a number of molecular analytical techniques. It was found that sustained release of the drug resulted in better bioavailability. In addition, the designed formulation demonstrated high biocompatibility with mouse fibroblast cells. The anti-TB activity of the nanodelivery formulation was determined using whole-cell resazurin microtiter plate assay, mo...
Research Interests:
With the emergence of extensively drug-resistant tuberculosis, there is a need for new anti-tubercular drugs that work through novel mechanisms of action. The meta cleavage product hydrolase, HsaD, has been demonstrated to be critical for... more
With the emergence of extensively drug-resistant tuberculosis, there is a need for new anti-tubercular drugs that work through novel mechanisms of action. The meta cleavage product hydrolase, HsaD, has been demonstrated to be critical for the survival of Mycobacterium tuberculosis in macrophages and is encoded in an operon involved in cholesterol catabolism, which is identical in M. tuberculosis and M. bovis BCG. We generated a mutant strain of M. bovis BCG with a deletion of hsaD and tested its growth on cholesterol. Using a fragment based approach, over 1000 compounds were screened by a combination of differential scanning fluorimetry, NMR spectroscopy and enzymatic assay with pure recombinant HsaD to identify potential inhibitors. We used enzymological and structural studies to investigate derivatives of the inhibitors identified and to test their effects on growth of M. bovis BCG and M. tuberculosis. The hsaD deleted strain was unable to grow on cholesterol as sole carbon source...
Research Interests:
The neuroleptic drug thioridazine has been recently repositioned as possible anti-tubercular drug. Thioridazine showed anti-tubercular activity against drug resistant mycobacteria but it is endowed with adverse side effects. A small... more
The neuroleptic drug thioridazine has been recently repositioned as possible anti-tubercular drug. Thioridazine showed anti-tubercular activity against drug resistant mycobacteria but it is endowed with adverse side effects. A small library of thioridazine derivatives has been designed through the replacement of the piperidine and phenothiazine moieties, with the aim to improve the anti-tubercular activity and to reduce the cytotoxic effects. Among the resulting compounds, the indole derivative 12e showed an antimycobacterial activity significantly better than thioridazine and a cytotoxicity 15-fold lower.
Research Interests:
Research Interests:
Research Interests: Polymorphism, Biological Sciences, Tuberculosis, Mycobacterium, Stress response, and 15 moreSalmonella Typhimurium, Enzyme, Arylamine N-acetyltransferase, Active site, Genetic Polymorphism, Molecular Conformation, Amino Acid Sequence, Cell Wall, Reaction Mechanism, Isoniazid, M. smegmatis, M. marinum, Arylamine, Molecular Sequence Data, and Pharmacology and pharmaceutical sciences
The first total synthesis of the marine natural products Psammaplin C and Tokaradine A is described. Benzylidene rhodanines were utilized as versatile intermediates toward the synthesis of seven brominated marine sponge metabolites... more
The first total synthesis of the marine natural products Psammaplin C and Tokaradine A is described. Benzylidene rhodanines were utilized as versatile intermediates toward the synthesis of seven brominated marine sponge metabolites through the optimization of protection group strategies. Spermatinamine demonstrated good inhibition of all cancer cell lines tested, in particular the leukemia K562 and colon cancer HT29 cell lines.
Research Interests:
ABSTRACT Analysis of the phytochemical and antimicrobial properties of Mallotus phillipensis revealed rottlerin (1) as the primary active agent in a chloroform extract from the plant. Rottlerin had notable activities against... more
ABSTRACT Analysis of the phytochemical and antimicrobial properties of Mallotus phillipensis revealed rottlerin (1) as the primary active agent in a chloroform extract from the plant. Rottlerin had notable activities against Staphylococcus aureus (0.625–4µg/ml) and good to moderate activities against Escherichia coli (32µg/ml) and Mycobacteriun bovis (100µg/ml) respectively. Remarkably, rottlerin at sub-inhibitory concentrations inhibited by &gt;1000-fold the transfer of broad-host range plasmid pKM101 between E. coli isolates. The anti-plasmid activity appeared to be specific, the transfer plasmids of different types, such as TP114, were not inhibited by such the same extent although the complete range of activity has yet to be determined. Rottlerin appears to have dual properties: direct anti-bacterial activity and the capacity to inhibit antimicrobial resistance spread. This is vital in the fight against multi-resistant bacteria and exploiting the mechanism of plasmid transfer could potentially lead to the development of more universal antimicrobial agents.
Research Interests:
The number of cases of drug-resistant Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has risen rapidly in recent years. This has led to the resurgence in repurposing existing drugs, such as non-steroidal... more
The number of cases of drug-resistant Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has risen rapidly in recent years. This has led to the resurgence in repurposing existing drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), for anti-TB treatment. Evidence from novel drug screening in vitro, in vivo, pharmacokinetic/pharmacodynamics analyses and clinical trials has been used for the preparation of this systematic review of the potential of NSAIDs for use as an adjunct in new TB chemotherapies. Certain NSAIDs have demonstrated inhibitory properties towards actively replicating, dormant and drug-resistant clinical isolates of M. tuberculosis cells. NSAIDs are a diverse class of drugs, which have reported off-target activities, and their endogenous antimicrobial mechanism(s) of action is still unclear. It is essential that clinical trials of NSAIDs continue, in order to assess their suitability for addition to the current TB treatment regimen. Repurp...
Research Interests:
Research Interests:
Research Interests:
Design and Synthesis of 1-((1,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)-4-methylpi
Novel pyrroles have been designed, synthesized, and evaluated against mycobacterial strains. The pyrroles have originally been designed as hybrids of the antitubercular drugs BM212 (1) and SQ109 (2), which showed common chemical features... more
Novel pyrroles have been designed, synthesized, and evaluated against mycobacterial strains. The pyrroles have originally been designed as hybrids of the antitubercular drugs BM212 (1) and SQ109 (2), which showed common chemical features with very similar topological distribution. A perfect superposition of the structures of 1 and 2 revealed by computational studies suggested the introduction of bulky substituents at the terminal portion of the pyrrole C3 side chain and the removal of the C5 aryl moiety. Five compounds showed high activity toward Mycobacterium tuberculosis, while 9b and 9c were highly active also against multidrug-resistant clinical isolates. Compound 9c showed low eukaryotic cell toxicity, turning out to be an excellent lead candidate for preclinical trials. In addition, four compounds showed potent inhibition (comparable to that of verapamil) toward the whole-cell drug efflux pump activity of mycobacteria, thus turning out to be promising multidrug-resistance-reve...