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Replacement of the essential nitro group by electrophilic warheads towards nitro-free antimycobacterial benzothiazinones

ABSTRACT: Nitrobenzothiazinones (BTZs) are undergoing late-stage development as a novel class of potent antituberculotic drug candidates with two compounds in clinical phases. BTZs inhibit decaprenylphosphoryl-β-D-ribose oxidase 1 (DprE1), a key enzyme in cell wall biosynthesis of mycobacteria. Their mechanism of action involves an in-situ reduction of the nitro moiety to a reactive nitroso intermediate capable of covalent binding to Cys387 in the catalytic cavity. The electron-deficient nature of the aromatic core is a key driver for the formation of hydride-Meisenheimer complexes (HMC) as main metabolites in vivo. To mimic the electrophilic character of the nitroso moiety, bioisosteric replacement against electrophilic warheads was attempted to reduce HMC formation without compromising covalent reactivity. Herein, we synthesized and characterized a set of various covalent warheads covering different reaction principles. Covalent inhibition was confirmed for all antimycobacterial compounds by enzymatic inhibition assays and protein mass spectrometry analysis.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mycobacterium Tuberculosis Kt-0001

SUBMITTER: Thomas Krüger

LAB HEAD: Axel A. Brakhage

PROVIDER: PXD053165 | Pride | 2024-09-11

REPOSITORIES: Pride

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Project description:Aspergillus fumigatus can cause Invasive Pulmonary Aspergillosis (IPA), the most severe form of Aspergillus-related infections. Fungicidal azoles and fungistatic caspofungin (CAS) are the first- and second-line therapies, respectively, used to treat IPA. However, azole-resistance is on the rise and new therapeutic alternatives need to be implemented. Recently, we showed that treatment of A. fumigatus with CAS or micafungin, but not voriconazole, induces production of the oxylipin 5,8-diHODE by the fungal oxygenase PpoA. Here we investigated the influence of ppo genes, that encode fatty acid oxygenases responsible for oxylipin biosynthesis, on CAS tolerance. The ppo mutants showed a very complex pattern of CAS susceptibility. PpoA and PpoC influence on CAS tolerance is mediated by MpkA phosphorylation and protein kinase A (PKA) activity. RNAseq transcriptional profiling and label-free quantitative proteomics (spectral counts) of the ppoA, and ppoC mutants showed that differentially expressed genes and proteins are related to secondary metabolites and carbohydrate metabolism. We tested several mutants of these differentially expressed genes encoding transcription factors and signal transduction proteins and some of them are more susceptible to CAS. We also characterized two clinical isolates, CNM7555 and IFM41607, that have decreased and increased susceptibility to CAS. CNM7555 does not have increased oxylipin production in the presence of CAS while the oxylipin induction upon CAS exposure is increased in the IFM41607, suggesting oxylipins are not the single mechanism involved in CAS tolerance in these isolates. Upon CAS exposure, CNM7555 has increased MpkA phosphorylation and PKA activity than IFM41607. Modulation of secondary metabolite production and carbohydrate metabolism is also essential in these clinical isolates for acquiring CAS tolerance. Our results reveal different aspects and genetic determinants involved in A. fumigatus CAS tolerance.

			Action	DRS
	DprE1_DMSO-a.raw	Raw
	DprE1_DMSO-b.raw	Raw
	DprE1_DMSO-c.raw	Raw
	DprE1_DMSO.fasta	Fasta
	DprE1_DMSO.mgf	Mgf

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Replacement of the essential nitro group by electrophilic warheads towards nitro-free antimycobacterial benzothiazinones

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