Discovery of Substituted (2-Aminooxazol-4-yl)Isoxazole-3-carboxylic Acids as Inhibitors of Bacterial Serine Acetyltransferase in the Quest for Novel Potential Antibacterial Adjuvants.

Joana Magalhães,Gabriele Costantino,Nina Franko,Stefano Bettati,Clotilde Silvia Cabassi,Barbara Campanini,Päivi Tammela,Agostino Bruno,Stefano Armao,Marco Pieroni,Giannamaria Annunziato,Samanta Raboni,Andrea Mozzarelli,Costanza Spadini

doi:10.3390/ph14020174

Abstract

Many bacteria and actinomycetales use L-cysteine biosynthesis to increase their tolerance to antibacterial treatment and establish a long-lasting infection. In turn, this might lead to the onset of antimicrobial resistance that currently represents one of the most menacing threats to public health worldwide. The biosynthetic machinery required to synthesise L-cysteine is absent in mammals; therefore, its exploitation as a drug target is particularly promising. In this article, we report a series of inhibitors of Salmonella thyphimurium serine acetyltransferase (SAT), the enzyme that catalyzes the rate-limiting step of L-cysteine biosynthesis. The development of such inhibitors started with the virtual screening of an in-house library of compounds that led to the selection of seven structurally unrelated hit derivatives. A set of molecules structurally related to hit compound 5, coming either from the original library or from medicinal chemistry efforts, were tested to determine a preliminary structure–activity relationship and, especially, to improve the inhibitory potency of the derivatives, that was indeed ameliorated by several folds compared to hit compound 5 Despite these progresses, at this stage, the most promising compound failed to interfere with bacterial growth when tested on a Gram-negative model organism, anticipating the need for further research efforts.

Highlights

This article is an open access articleCysteine, which in mammals cannot be obtained via direct synthesis, is the main building block of many biomolecules and cofactors, such as S-adenosyl methionine, CoA, biotin, lipoic acid, and thiamin pyrophosphate, and it is the active portion of molecules with detoxifying properties such as glutathione and mycothiol
One of the most intriguing aspects of cysteine biosynthesis is its role in the development of antibiotic resistance, as reported in the case of S. typhimurium, where an impaired oxidative stress response due to the genetic inhibition of cysteine biosynthesis caused a decrease in antibiotic resistance in both vegetative and swarm cell populations [11]
Through an in-house library virtual screening combined with a medicinal chemistry campaign, we were able to identify the most potent inhibitor of StSAT known so far

Summary

Introduction

This article is an open access articleCysteine, which in mammals cannot be obtained via direct synthesis, is the main building block of many biomolecules and cofactors, such as S-adenosyl methionine, CoA, biotin, lipoic acid, and thiamin pyrophosphate, and it is the active portion of molecules with detoxifying properties such as glutathione and mycothiol. Pharmaceuticals 2021, 14, 174 must respond to nutrient starvation and/or oxidative stress occurring inside macrophages. In these challenging conditions, any interference with the adaptation strategies may lead to a reduction of their infectivity and to an increased susceptibility to antibacterial agents. Mutants bearing a deletion of cysteine biosynthetic enzymes were found to possess reduced virulence as in the case of cysH of M. tuberculosis [9] and cysI or cysK of B. melitensis [10], and/or an increased sensitivity to oxidative stress, like the mutant of cysI of B. melitensis [10]. 22d) at different positions the phenyl does not significantly most interesting are obtained thealthough phenyl ring is notinteresting substitutedresults Inhibitoryactivity activityof ofsynthesised synthesisedcompounds compounds21a–c, 21eand and a–e

Methods

Results

Discussion

Conclusion