Direct Inhibition of MmpL3 by Novel Antitubercular Compounds

Li, Wei; Stevens, Casey M.; Pandya, Amitkumar N.; Darżynkiewicz, Edward; Bhattarai, Pankaj; Tong, Weiwei; Gonzalez-Juarrero, Mercedes; North, E. Jeffrey; Zgurskaya, Helen I.; Jackson, Mary

doi:10.1021/acsinfecdis.9b00048

Cited by 79 publications

(150 citation statements)

References 35 publications

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“…The authors also showed that only SQ109 and BM212 dissipated both ∆pH and ∆Ψ (although the latter only at high concentrations). These assays could be a great tool for assessing the specificity of new and previously identified drugs that are believed to act against MmpL3 [105].…”

Section: Mmpl3: the Achilles Heel Of Mycobacterium Tuberculosismentioning

confidence: 99%

Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3

et al. 2020

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The development and spread of Mycobacterium tuberculosis multi-drug resistant strains still represent a great global health threat, leading to an urgent need for novel anti-tuberculosis drugs. Indeed, in the last years, several efforts have been made in this direction, through a number of high-throughput screenings campaigns, which allowed for the identification of numerous hit compounds and novel targets. Interestingly, several independent screening assays identified the same proteins as the target of different compounds, and for this reason, they were named “promiscuous” targets. These proteins include DprE1, MmpL3, QcrB and Psk13, and are involved in the key pathway for M. tuberculosis survival, thus they should represent an Achilles’ heel which could be exploited for the development of novel effective drugs. Indeed, among the last molecules which entered clinical trials, four inhibit a promiscuous target. Within this review, the two most promising promiscuous targets, the oxidoreductase DprE1 involved in arabinogalactan synthesis and the mycolic acid transporter MmpL3 are discussed, along with the latest advancements in the development of novel inhibitors with anti-tubercular activity.

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Section: Mmpl3: the Achilles Heel Of Mycobacterium Tuberculosismentioning

confidence: 99%

Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3

et al. 2020

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“…In Mycobacteria, two independentlysynthesized fatty acids, the short alpha branch (C24-C26) and long meromycolate chain (C50-C60), produced by the single FAS-I enzyme and FAS-II complex (12,13), respectively, are modified then condensed by the cytoplasmic polyketide synthase, Pks13 (14), to form a 2alkyl 3-keto fatty acid which is then reduced by CmrA to generate the mature, hydroxylated mycolic acid (15). These fatty acids are conjugated to trehalose to form TMM which is then bound and flipped to the periplasm by the integral membrane lipid transporter MmpL3 (16,17), the target of several classes of new antimycobacterial inhibitors (18,19). While structurally diverse classes of MmpL3 inhibitors have been reported, several of these compounds were subsequently found to indirectly inhibit MmpL3, by disrupting the transmembrane electrochemical proton gradient (20).…”

Section: _____________________________________mentioning

confidence: 99%

MtrP, a putative methyltransferase in Corynebacteria, is required for optimal membrane transport of trehalose mycolates

Rainczuk

Klatt

Yamaryo‐Botté

et al. 2020

Journal of Biological Chemistry

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Pathogenic bacteria of the genera Mycobacterium and Corynebacterium cause severe human diseases such as tuberculosis (Mycobacterium tuberculosis) and diphtheria (Corynebacterium diphtheriae). The cells of these species are surrounded by protective cell walls rich in long-chain mycolic acids. These fatty acids are conjugated to the disaccharide trehalose on the cytoplasmic side of the bacterial cell membrane. They are then transported across the membrane to the periplasm where they act as donors for other reactions. We have previously shown that transient acetylation of the glycolipid trehalose monohydroxycorynomycolate (hTMCM) enables its efficient transport to the periplasm in Corynebacterium glutamicum and that acetylation is mediated by the membrane protein TmaT. Here, we show that a putative methyltransferase, encoded at the same genetic locus as TmaT, is also required for optimal hTMCM transport. Deletion of the C. glutamicum gene NCgl2764 (Rv0224c in M. tuberculosis) abolished acetyltrehalose monocorynomycolate (AcTMCM) synthesis, leading to accumulation of hTMCM in the inner membrane and delaying its conversion to trehalose dihydroxycorynomycolate (h2TDCM). Complementation with NCgl2764 normalized turnover of hTMCM to h2TDCM. In contrast, complementation with NCgl2764 derivatives mutated at residues essential for methyltransferase activity failed to rectify the defect, suggesting that NCgl2764/Rv0224c encodes a methyltransferase, designated here as MtrP. Comprehensive analyses of the individual mtrP and tmaT mutants and of a double mutant revealed strikingly similar changes across several lipid classes compared with WT bacteria. These findings indicate that both MtrP and TmaT have nonredundant roles in regulating AcTMCM synthesis, revealing additional complexity in the regulation of trehalose mycolate transport in the Corynebacterineae.

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“…MmpL3 is suggested as one of the main targets of the compound in both organisms. Indeed, some mutations in the MmpL3 gene results in the emergence of the resistant strains [ 7 , 23 ]. The crystal structure of Msm MmpL3 in complex with SQ109 (PDB ID: 6AJG) showed that the drug disrupted core Asp-Tyr pairs (D256-Y646 and Y257-D645), apparently crucial for protein function [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Hydroxylation of Antitubercular Drug Candidate, SQ109, by Mycobacterial Cytochrome P450

Bukhdruker

Varaksa

Grabovec

et al. 2020

IJMS

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Spreading of the multidrug-resistant (MDR) strains of the one of the most harmful pathogen Mycobacterium tuberculosis (Mtb) generates the need for new effective drugs. SQ109 showed activity against resistant Mtb and already advanced to Phase II/III clinical trials. Fast SQ109 degradation is attributed to the human liver Cytochrome P450s (CYPs). However, no information is available about interactions of the drug with Mtb CYPs. Here, we show that Mtb CYP124, previously assigned as a methyl-branched lipid monooxygenase, binds and hydroxylates SQ109 in vitro. A 1.25 Å-resolution crystal structure of the CYP124–SQ109 complex unambiguously shows two conformations of the drug, both positioned for hydroxylation of the ω-methyl group in the trans position. The hydroxylated SQ109 presumably forms stabilizing H-bonds with its target, Mycobacterial membrane protein Large 3 (MmpL3). We anticipate that Mtb CYPs could function as analogs of drug-metabolizing human CYPs affecting pharmacokinetics and pharmacodynamics of antitubercular (anti-TB) drugs.

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Direct Inhibition of MmpL3 by Novel Antitubercular Compounds

Cited by 79 publications

References 35 publications

Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3

Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3

MtrP, a putative methyltransferase in Corynebacteria, is required for optimal membrane transport of trehalose mycolates

Hydroxylation of Antitubercular Drug Candidate, SQ109, by Mycobacterial Cytochrome P450

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