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TBAJ-876 Retains Bedaquiline's Activity against Subunits c and ? of Mycobacterium tuberculosis F-ATP Synthase.

ABSTRACT: The antituberculosis drug bedaquiline (BDQ) inhibits Mycobacterium tuberculosis F-ATP synthase by interfering with two subunits. Drug binding to the c subunit stalls the rotation of the c ring, while binding to the ? subunit blocks coupling of c ring rotation to ATP synthesis at the catalytic ?3:?3 headpiece. BDQ is used for the treatment of drug-resistant tuberculosis. However, the drug is highly lipophilic, displays a long terminal half-life, and has a cardiotoxicity liability by causing QT interval prolongation. Recent medicinal chemistry campaigns have resulted in the discovery of 3,5-dialkoxypyridine analogues of BDQ that are less lipophilic, have higher clearance, and display lower cardiotoxic potential. TBAJ-876, which is a new developmental compound of this series, shows attractive antitubercular activity and efficacy in a murine tuberculosis model. Here, we asked whether TBAJ-876 and selected analogues of the compound retain BDQ's mechanism of action. Biochemical assays showed that TBAJ-876 is a potent inhibitor of mycobacterial F-ATP synthase. Selection of spontaneous TBAJ-876-resistant mutants identified missense mutations at BDQ's binding site on the c subunit, suggesting that TBAJ-876 retains BDQ's targeting of the c ring. Susceptibility testing against a strain overexpressing the ? subunit and a strain harboring an engineered mutation in BDQ's ? subunit binding site suggest that TBAJ-876 retains BDQ's activity on the ? subunit. Nuclear magnetic resonance (NMR) titration studies confirmed that TBAJ-876 binds to the ? subunit at BDQ's binding site. We show that TBAJ-876 retains BDQ's antimycobacterial mode of action. The developmental compound inhibits the mycobacterial F-ATP synthase via a dual-subunit mechanism of interfering with the functions of both the enzyme's c and ? subunits.

SUBMITTER: Sarathy JP

PROVIDER: S-EPMC6761534 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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TBAJ-876 Retains Bedaquiline's Activity against Subunits c and ε of Mycobacterium tuberculosis F-ATP Synthase.

Sarathy Jickky Palmae JP Ragunathan Priya P Shin Joon J Cooper Christopher B CB Upton Anna M AM Grüber Gerhard G Dick Thomas T

Antimicrobial agents and chemotherapy 20190923 10

The antituberculosis drug bedaquiline (BDQ) inhibits Mycobacterium tuberculosis F-ATP synthase by interfering with two subunits. Drug binding to the c subunit stalls the rotation of the c ring, while binding to the ε subunit blocks coupling of c ring rotation to ATP synthesis at the catalytic α3:β3 headpiece. BDQ is used for the treatment of drug-resistant tuberculosis. However, the drug is highly lipophilic, displays a long terminal half-life, and has a cardiotoxici ...[more]

PMID: 31358589

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Project description:Dormant Mycobacterium tuberculosis bacilli are believed to play an important role in latent tuberculosis infection. Previously, we have demonstrated that cultivation of M. tuberculosis in K(+)-deficient medium resulted in generation of dormant cells. These bacilli were non-culturable on solid media (a key feature of dormant M. tuberculosis in vivo) and characterized by low metabolism and tolerance to anti-tuberculosis drugs. The dormant bacteria demonstrated a high potential to reactivation after K(+) reintroduction even after prolonged persistence under rifampicin. In this work, we studied the transcriptome and stability of transcripts in persisting dormant bacilli under arrest of mRNA de novo synthesis.RNA-seq-based analysis of the dormant non-culturable population obtained under rifampicin exposure revealed a 30-50-fold decrease of the total mRNA level, indicating global transcriptional repression. However, the analysis of persisting transcripts displayed a cohort of mRNA molecules coding for biosynthetic enzymes, proteins involved in adaptation and repair processes, detoxification, and control of transcription initiation. This 'dormant transcriptome' demonstrated considerable stability during M. tuberculosis persistence and mRNA de novo synthesis arrest. On the contrary, several small non-coding RNAs showed increased abundance on dormancy. Interestingly, M. tuberculosis entry into dormancy was accompanied by the cleavage of 23S ribosomal RNA at a specific point located outside the ribosome catalytic center.Dormant non-culturable M. tuberculosis bacilli are characterized by a global transcriptional repression. At the same time, the dormant bacilli retain low-abundant mRNAs, which are considerably stable during in vitro persistence, reflecting their readiness for translation upon early resuscitation steps. Increased abundance of non-coding RNAs on dormancy may indicate their role in the entry into and maintenance of M. tuberculosis dormant non-culturable state.

Dataset Information

TBAJ-876 Retains Bedaquiline's Activity against Subunits c and ? of Mycobacterium tuberculosis F-ATP Synthase.

Publications

TBAJ-876 Retains Bedaquiline's Activity against Subunits c and ε of <i>Mycobacterium tuberculosis</i> F-ATP Synthase.

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