HC2091 kills Mycobacterium tuberculosis by targeting the MmpL3 mycolic acid transporter
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA420343 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6329094.fastq.gz | Fastqsanger.gz | |||
| SRR6329095.fastq.gz | Fastqsanger.gz | |||
| SRR6329096.fastq.gz | Fastqsanger.gz | |||
| SRR6329097.fastq.gz | Fastqsanger.gz | |||
| SRR6329098.fastq.gz | Fastqsanger.gz |
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Project description:The spread of antibiotic resistance is a major challenge for treatment of Mycobacterium tuberculosis infection. In addition, efficacy of drugs is often limited by the restricted permeability of the mycomembrane. Frontline antibiotics inhibit mycomembrane biosynthesis leading to rapid cell death. Inspired by this mechanism we exploit β-lactones as putative mycolic acid mimics to block serine hydrolases involved in their biosynthesis. Among a collection of β-lactones we found one hit with potent anti-mycobacterial and bactericidal activity. Chemical proteomics using an alkynylated probe identified Pks13 and Ag85 serine hydrolases as major targets. Validation via enzyme assays and customized 13C metabolite profiling showed that both targets are functionally impaired by the β-lactone. Co-administration with front-line antibiotics enhanced the potency against M. tuberculosis by more than 100-fold demonstrating a therapeutic potential of targeting mycomembrane biosynthesis serine hydrolases.
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Project description:Treatment of Mycobacterium tuberculosis infections is a challenging task due to a growing number of resistant clinical isolates as well as an almost empty drug development pipeline. To identify new antibiotic hits, we screened a focused library of 400 synthetic compounds derived from a recently discovered molecule with promising anti-mycobacterial activity. A suite of more potent hit molecules was deciphered with sub-micromolar activity. Utilising tailored affinity-based probes for chemical proteomic investigations, we successfully pinpointed the mycolic acid transporter MmpL3 and two epoxide hydrolases, EphD and EphF, also linked to mycolic acid biosynthesis, as specific targets of the compounds. These targets were thoroughly and independently validated by activity assays, under- and overexpression, resistance generation, and proteomic studies. Structural refinement of the most potent hit molecules led to the development of a new lead compound that demonstrates enhanced biological activity in M. tuberculosis, low human cytotoxicity, and improved solubility and oral bioavailability − traits that are often challenging to achieve with anti-mycobacterial drugs. Overall, drug-likeness, as well as the dual mode of action, addressing the mycolic acid cell wall assembly at two distinct steps, holds significant potential for further in vivo applications.
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Project description:The purpose of this study was to characterize the mechanism of action of the small molecule HC2091
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Project description:Tuberculosis, caused by the intracellular pathogen Mycobacterium tuberculosis, is a deadly disease that requires a long course of treatment. The emergence of drug-resistant strains has driven efforts to discover new small molecules that can kill the bacterium. Here, we report characterizations of the compound HC2091, which kills M. tuberculosis in a time- and dose-dependent manner in vitro and inhibits M. tuberculosis growth in macrophages. Whole-genome sequencing of spontaneous HC2091-resistant mutants identified single-nucleotide variants in the mmpL3 mycolic acid transporter gene. HC2091-resistant mutants do not exhibit cross-resistance with the well-characterized Mycobacterium membrane protein large 3 (MmpL3) inhibitor SQ109, suggesting a distinct mechanism of interaction with MmpL3. Additionally, HC2091 does not modulate bacterial membrane potential or kill nonreplicating M. tuberculosis, thus acting differently from other known MmpL3 inhibitors. RNA sequencing (RNA-seq) transcriptional profiling and lipid profiling of M. tuberculosis treated with HC2091 or SQ109 show that the two compounds target a similar pathway. HC2091 has a chemical structure dissimilar to those of previously described MmpL3 inhibitors, supporting the notion that HC2091 is a new class of MmpL3 inhibitor.
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Project description:Mycobacterium tuberculosis has a complex cell envelope that is remodelled throughout infection to respond and survive the hostile and variable intracellular conditions within the host. Despite the importance of cell wall homeostasis in pathogenicity, little is known about the environmental signals and regulatory networks controlling cell wall biogenesis in mycobacteria. The mycolic acid desaturase regulator (MadR) is a transcriptional repressor responsible for regulation of the essential aerobic desaturases desA1 and desA2 that are differentially regulated throughout infection along with mycolate modification genes and thus, likely involved in mycolic acid remodelling. Here we generated a madR null mutant in M. smegmatis that exhibited traits of an impaired cell wall with increased permeability, susceptibility to rifampicin and cell surface disruption as a consequence of desA1/desA2 dysregulation. Analysis of mycolic acids revealed the presence of a highly desaturated mycolate in the null mutant that exists in relative trace amounts in the wildtype, but increases in abundance upon cell surface disruption as a result of relieved repression on the desA1/desA2 promoters. Transcriptomic profiling confirmed MadR as a cell surface disruption responsive regulator of desA1/desA2 and further implicating it in the control of bespoke β-oxidation pathways and transport evolutionarily diversified subnetworks associated with virulence. In vitro characterisation of MadR using electromobility shift assays and analysis of binding affinities is suggestive of a unique acyl-CoA pool sensing mechanism, whereby MadR is able to bind a range of acyl-CoA but MadR repression of desA1/desA2 promoters is only relieved upon binding of saturated acyl-CoA of chain length C16-C24. We propose this acyl effector ligand mechanism as distinct to other regulators of mycolic acid biosynthesis or fatty acid desaturases and places MadR as the key regulatory checkpoint that coordinates mycolic acid remodelling in response to host derived cell surface perturbation
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Project description:Monocyte exhaustion characterized by sustained pathogenic inflammatory and immune-suppressive features underlies the pathogenesis of sepsis induced by systemic polymicrobial infections. However, effective strategies in blocking monocyte exhaustion and restoring innate homeostasis are currently not available. In this study, we found that Methoxy-Mycolic Acid (M-MA), a branched mycolic acid derived from Mycobacterium Bovis Bacillus Calmette–Guérin (BCG), to be a potent agent in alleviating monocyte exhaustion and restoring immune homeostasis. Co-treatment of monocytes with M-MA can effectively block the expansion of exhausted Ly6Chi /CD38hi/PD-L1hi monocytes induced by repetitive LPS challenges, and restore the expression of immune-enhancing CD86 on co-treated monocytes. Functionally, M-MA treatment restored mitochondrial functions of exhausted monocytes and alleviated their suppressive activities on co-cultured T cells. Mechanistically, M-MA exerts its protective effects independent of cellular receptor TREM2, and relieves cellular stress signaling through blocking Src-STAT1 mediated pathogenic inflammatory polarization as well as reducing the production of compensatory immune suppressors TAX1BP1 and PLAC8. Our whole genome methylation analyses further revealed that M-MA can effectively erase methylation memory of exhausted monocytes, with validated restoration of plac8 methylation by M-MA. Together, our data reveal M-MA as a potent agent in restoring monocyte homeostasis with future therapeutic potential for the treatment of sepsis.
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