Molecular Mechanisms of MmpL3 Function and Inhibition

Williams, John T.; Abramovitch, Robert B.

doi:10.1089/mdr.2021.0424

Cited by 10 publications

(4 citation statements)

References 220 publications

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“…MTB has fifteen genes coding for RND-type transporters, 13 of which are from Mmpl proteins. In addition to the transport of lipids, these transporters have also been involved in the transportation of drugs, the acquisition of iron and the export of siderophores [75][76][77][78][79][80][81][82].…”

Section: Mycobacteria and Mycobacterium Tuberculosis: An Interesting ...mentioning

confidence: 99%

The <em>Mycobacterium tuberculosis</em>: A Silent Killer

Oliveira,

Ferreira,

Matta

et al. 2023

Preprint

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Mycobacterium tuberculosis is the agent of tuberculosis, one of the most important infectious diseases in the world. This microorganism stands out from other bacteria, not only for its extremely high infection capacity, but also for its cellular characteristics that include an extremely resistant and hydrophobic cellular parade the passage of antibiotics. An incredible ability to adapt to adverse conditions inside the host as well as its vast arsenal of virulence factors that allow its survival within the inhospitable environment within the macrophage can be highlighted. This review aims to discuss several aspects of MTB microbiology, genetics, and physiology. We will address in this review details of the metabolism of MTB that allows it to replicate in the active phase and remain viable during latency, as well as the characteristics of its cell wall that contribute to the blockade of the immune response and its resistance to antibiotics.

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Section: Mycobacteria and Mycobacterium Tuberculosis: An Interesting ...mentioning

confidence: 99%

The <em>Mycobacterium tuberculosis</em>: A Silent Killer

Oliveira,

Ferreira,

Matta

et al. 2023

Preprint

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“…The evolution of multi-drug resistance (MDR) and extensively drug-resistant strains of Mtb, which spread person-to-person ( 1 ), requires the development of new therapeutic strategies with novel mechanisms of action (MOA). The essential mycolic acid flippase ( 2 ) MmpL3 has been identified as a new potential target for TB therapy ( 3 – 20 ) with more than 20 different chemical scaffolds reported ( 21 ). SQ109, the most clinically advanced MmpL3 inhibitor, completed a Phase IIb clinical trial in 2018 ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

“…Other MmpL3 inhibitors, sharing some structural features relative to HC2099, have been described in the literature ( 28 ). These include the 1H-benzimidazole MmpL3 inhibitors EJMCh4 and EJMCh6, which are potent inhibitors against both Mtb and NTMs ( 8 , 29 ).…”

Section: Introductionmentioning

confidence: 99%

The Mycobacterium tuberculosis MmpL3 inhibitor MSU-43085 is active in a mouse model of infection

Williams,

Giletto,

Haiderer

et al. 2024

Microbiol Spectr

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Addressing drug resistance in Mycobacterium tuberculosis (Mtb) requires the development of new drugs with new targets. We previously identified 13 MmpL3 inhibitors from a screen of a small library of Mtb growth inhibitors. In this report, we describe the biological activities of a set of HC2099 analogs active against Mtb in vitro , intracellular Mtb, as well as M. abscessus and M. avium . Pharmacokinetic (PK) studies identified MSU-43085 as orally bioavailable with a short half-life. High dosing (100 mg/kg) saturates clearance processes, enabling efficacy studies. The results of an in vivo efficacy study found that MSU-43085 was active against Mtb in an acute murine TB infection model but lacked activity in a chronic murine TB infection model. The results of this study serve as a proof of concept for this series and support further optimizations of the HC2099 series of MmpL3 inhibitors. IMPORTANCE MmpL3 is a protein that is required for the survival of bacteria that cause tuberculosis (TB) and nontuberculous mycobacterial (NTM) infections. This report describes the discovery and characterization of a new small molecule, MSU-43085, that targets MmpL3 and is a potent inhibitor of Mycobacterium tuberculosis (Mtb) and M. abscessus survival. MSU-43085 is shown to be orally bioavailable and efficacious in an acute model of Mtb infection. However, the analog is inactive against Mtb in chronically infected mice. Pharmacokinetic and metabolite identification studies identified in vivo metabolism of MSU-43085, leading to a short half-life in treated mice. These proof-of-concept studies will guide further development of the MSU-43085 series for the treatment of TB or NTM infections.

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“…Identification molecular mediators involved in the pathogenesis of a disease or in infection control can have a myriad of applications including—establishment of diagnostic biomarkers, discovery of novel drug targets, identification of biomarkers for monitoring treatment regimens and assignments of correlates of protection (CoP) for vaccines and vaccine candidates. Currently for drug development against Mycobacterium tuberculosis , designated prime targets include DNA gyrase ( Mdluli and Ma, 2008 ), Leu tRNA synthetase, ATP synthase and proteins involved in cell wall synthesis like DprE1 and MmpL3 ( Williams & Abramovitch, 2023 ) ( Dartois & Rubin, 2022 ). As for novel targets for drug discovery, KatG, Clp proteases, Menaquinone and KatG have shown great prospects ( Bose et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Advances in computational frameworks in the fight against TB: The way forward

Naidu

Nayak

et al. 2023

Front. Pharmacol.

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Around 1.6 million people lost their life to Tuberculosis in 2021 according to WHO estimates. Although an intensive treatment plan exists against the causal agent, Mycobacterium Tuberculosis, evolution of multi-drug resistant strains of the pathogen puts a large number of global populations at risk. Vaccine which can induce long-term protection is still in the making with many candidates currently in different phases of clinical trials. The COVID-19 pandemic has further aggravated the adversities by affecting early TB diagnosis and treatment. Yet, WHO remains adamant on its “End TB” strategy and aims to substantially reduce TB incidence and deaths by the year 2035. Such an ambitious goal would require a multi-sectoral approach which would greatly benefit from the latest computational advancements. To highlight the progress of these tools against TB, through this review, we summarize recent studies which have used advanced computational tools and algorithms for—early TB diagnosis, anti-mycobacterium drug discovery and in the designing of the next-generation of TB vaccines. At the end, we give an insight on other computational tools and Machine Learning approaches which have successfully been applied in biomedical research and discuss their prospects and applications against TB.

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Molecular Mechanisms of MmpL3 Function and Inhibition

Cited by 10 publications

References 220 publications

The <em>Mycobacterium tuberculosis</em>: A Silent Killer

The <em>Mycobacterium tuberculosis</em>: A Silent Killer

The Mycobacterium tuberculosis MmpL3 inhibitor MSU-43085 is active in a mouse model of infection

Advances in computational frameworks in the fight against TB: The way forward

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