A5027369728- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Cancer therapeutics and mechanisms
- Antibiotic Resistance in Bacteria
- CRISPR and Genetic Engineering
- ATP Synthase and ATPases Research
- Synthesis and biological activity
- RNA and protein synthesis mechanisms
- Bacterial Genetics and Biotechnology
- Phenothiazines and Benzothiazines Synthesis and Activities
- Peptidase Inhibition and Analysis
- Bioactive Compounds and Antitumor Agents
- Microbial Natural Products and Biosynthesis
- Quinazolinone synthesis and applications
- Biochemical and Molecular Research
- Protease and Inhibitor Mechanisms
- Evolution and Genetic Dynamics
- interferon and immune responses
- Multicomponent Synthesis of Heterocycles
- Bacterial biofilms and quorum sensing
- Ubiquitin and proteasome pathways
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Pharmaceutical and Antibiotic Environmental Impacts
- Probiotics and Fermented Foods
- Blood Coagulation and Thrombosis Mechanisms
University of Otago
2014-2025
Abstract The increasing incidence of drug resistance in Mycobacterium tuberculosis has diminished the efficacy almost all available antibiotics, complicating efforts to combat spread this global health burden. Alongside development new drugs, optimised combinations are needed improve treatment success and prevent further antibiotic resistance. Typically, leads reduced sensitivity, yet some cases evolution can lead enhanced sensitivity unrelated drugs. This phenomenon collateral is largely...
The bioenergetic mechanisms by which Mycobacterium tuberculosis survives hypoxia are poorly understood. Current models assume that the bacterium shifts to an alternate electron acceptor or fermentation maintain membrane potential and ATP synthesis. Counterintuitively, we find here oxygen itself is principal terminal during hypoxic dormancy. M. can metabolize efficiently at least two orders of magnitude below concentration predicted occur in lung granulomas. Despite a difference apparent...
ABSTRACT Mammalian cells produce many proteins, such as IFITM3, ISG15, MxA, and viperin, that inhibit influenza A virus (IAV) infection. Here, we show a new class of host protein, histone deacetylase 6 (HDAC6), inhibits IAV We found HDAC6-overexpressing release about 3-fold less progeny, whereas HDAC6-depleted 6-fold more progeny. The activity HDAC6 played role in its anti-IAV function tubacin, specific small-molecule inhibitor HDAC6, increased the progeny dose-dependent manner. Further,...
Respiration is a promising target for the development of new antimycobacterial agents, with growing number compounds in clinical entering this space. However, more candidate inhibitors are needed to expand therapeutic options available drug-resistant Mycobacterium tuberculosis infection. Here, we characterize putative respiratory complex III (QcrB) inhibitor, TB47: pyrazolo[1,5-a]pyridine-3-carboxamide. TB47 active (MIC between 0.016 and 0.500 μg/mL) against panel 56 M. isolates, including...
Metastasis is the cause of death in majority (∼90%) malignant cancers. The oral potassium-sparing diuretic amiloride and its 5-substituted derivative 5-N,N-(hexamethylene)amiloride (HMA) reportedly show robust antitumor/metastasis effects multiple vitro animal models. These are likely due, at least part, to inhibition urokinase plasminogen activator (uPA), a key protease determinant cell invasiveness metastasis. This study reports discovery 6-substituted HMA analogs that nanomolar potency...
Increasing antimicrobial resistance compels the search for next-generation inhibitors with differing or multiple molecular targets. In this regard, energy conservation in Mycobacterium tuberculosis has been clinically validated as a promising new drug target combatting drug-resistant strains of M. tuberculosis. Here, we show that HM2-16F, 6-substituted derivative FDA-approved amiloride, is an anti-tubercular inhibitor bactericidal properties comparable to bedaquiline (BDQ; Sirturo®) and...
Drug-resistant strains of Mycobacterium tuberculosis are a major global health problem. Resistance to the front-line antibiotic isoniazid is often associated with mutations in katG-encoded bifunctional catalase-peroxidase. We hypothesise that perturbed KatG activity would generate collateral vulnerabilities isoniazid-resistant katG mutants, providing potential pathway targets combat resistance. Whole genome CRISPRi screens, transcriptomics, and metabolomics were used genome-wide map cellular...
Bedaquiline is the cornerstone of a new regimen for treatment drug-resistant tuberculosis. However, its clinical use threatened by emergence bedaquiline-resistant strains Mycobacterium targets mycobacterial ATP synthase but predominant route to bedaquiline resistance via upregulation MmpS5L5 efflux pump due mutations that inactivate transcriptional repressor Rv0678. Here, we show reduces susceptibility as well new, more potent derivative TBAJ-876 and other antimicrobial substrates, including...
To investigate the structure of mycobacterial oxidative phosphorylation machinery, we prepared inverted membrane vesicles from Mycobacterium smegmatis , enriched for containing complexes interest, and imaged with electron cryomicroscopy. We show that this analysis allows determination both ATP synthase supercomplex respiratory III IV in their native membrane. The latter reveals enzyme malate:quinone oxidoreductase (Mqo) physically associates supercomplex, an interaction is lost on extraction...
Quinolinequinones (QQ) have been shown to inhibit the growth of mycobacterial species, but their mode(s) action and molecular target(s) remain unknown. To facilitate further development QQ as antimycobacterial drugs, we investigated mechanism target in mycobacteria. Cell viability Mycobacterium tuberculosis bovis bacillus Calmette–Guérin was determined presence QQ8c, a representative compound, isoniazid, frontline antitubercular drug. The effect QQ8c on energetics studied using inverted...
Bedaquiline is a newly developed anti-tuberculosis drug, conditionally approved by the United States Food and Drug Administration (USFDA) for treating drug-resistant tuberculosis in adults. Oral delivery of bedaquiline causes severe side effects such as increased hepatic aminotransferase levels cardiac arrhythmias (prolongation QT-interval). This study aimed to develop inhalable dry powder particles with high aerosolization efficiency reduce side-effects oral bedaquiline. (with or without...
Mycobacterium tuberculosis remains a leading cause of death for which new drugs are needed. The identification drug targets has been advanced by high-throughput and targeted genetic deletion strategies. Each though limitations including the inability to distinguish between levels vulnerability, lethality, scalability as molecular tool. Using mycobacterial CRISPR interference in combination with phenotypic screening, we have overcome these individual issues investigate essentiality,...
The dynamic interaction of the N- and C-terminal domains mycobacterial F-ATP synthase subunit ε is proposed to contribute efficient coupling H+-translocation ATP synthesis. Here, we investigate crosstalk between both by introducing chromosomal atpC missense mutations in helix 2 predicted disrupt inter domain ε-α therefore coupling. mutant εR105A,R111A,R113A,R115A (ε4A) showed decreased intracellular ATP, slower growth rates lower molar yields on non-fermentable carbon sources. Cellular...
Ohmyungsamycin A and ecumicin are structurally related cyclic depsipeptide natural products that possess activity against Mycobacterium tuberculosis (Mtb), the causative agent of (TB). Herein, we describe design synthesis a library analogues these two using an efficient solid-phase late-stage macrolactamization strategy. Lead possessed potent Mtb in vitro (minimum inhibitory concentration 125-500 nM) were shown to inhibit protein degradation by mycobacterial ClpC1-ClpP1P2 protease with...
The formation of biofilms provides a formidable defense for many bacteria against antibiotics and host immune responses. As consequence, are thought to be the root cause most chronic infections, including those occurring on medical indwelling devices, endocarditis, urinary tract diabetic burn wounds, bone joint infections. In cystic fibrosis (CF), Pseudomonas aeruginosa (P. aeruginosa) respiratory infections leading morbidity mortality in adults. Previous studies have shown that can undergo...
Mycobacterium tuberculosis remains a leading cause of infectious disease morbidity and mortality for which new drug combination therapies are needed. Combinations respiratory inhibitors can have synergistic or synthetic lethal interactions with sterilizing activity, suggesting that regimens multiple bioenergetic could shorten treatment times. However, realizing this potential requires an understanding combinations complexes, when inhibited, the strongest consequences on bacterial growth...
A revised total synthesis of aurachin D (1a), an isoprenoid quinolone alkaloid that targets Mycobacterium tuberculosis (Mtb) cytochrome bd (cyt-bd) oxidase, was accomplished using oxazoline ring-opening reaction. The ring opening enabled access to a range electron-poor analogues, while electron-rich analogues could be prepared the Conrad-Limpach aryl-substituted and side-chain-modified were screened for inhibition Mtb cyt-bd oxidase growth Mtb. Nanomolar observed shorter-chain analogue 1d...
There is an urgent need for novel drugs that target unique cellular pathways to combat infections caused by Mycobacterium tuberculosis. CRISPR interference (CRISPRi)-mediated transcriptional repression has recently been developed use in mycobacteria as a genetic tool identifying and validating essential genes drug targets. Whilst CRISPRi applied extracellular bacteria, no studies date have determined whether can be used M. tuberculosis infection models.Using the human monocytic...