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The development of the so-called antibiotic adjuvants as inhibitors of non-essential targets represents an innovative and attractive approach to counteract antimicrobial resistance (AMR). Most bacteria rely on the reductive sulfate assimilation pathway (RSAP) to synthesize cysteine, which is a building block for many important biomolecules. Cysteine biosynthetic enzymes are colonization factors that are dispensable during growth in rich media but might become indispensable during host colonization. Being this pathway absent in mammals, it might represent a promising target for drug intervention.We have focused our attention on compounds targeting serine acetyltransferase (SAT), which is one of the key enzymes involved in the l-cysteine biosynthesis, catalyzing the rate-limiting step of the whole process. In a previous communication, we have reported the discovery through a virtual screening of a new compound (1) with promising SAT inhibitory activity. The capability of this compound to interfere with bacterial growth in the cell assays prompted us to carry out a medicinal chemistry campaign to further investigate its potential. We herein report the synthesis of compound 1 analogues to define the structure–activity relationships (SAR) of this series of potential SAT inhibitors regarding the target binding and general toxicity. Despite the improvement in the inhibitory activity of some molecules, the toxicity profile needs to be fine-tuned, and these findings will be used to drive the synthesis of new analogues. more...

Antibacterial adjuvants are of great significance, since they allow one to downscale the therapeutic dose of conventional antibiotics and reduce the insurgence of antibacterial resistance. Herein, we report that O-acetylserine sulfhydrylase (OASS) inhibitors could be used as colistin adjuvants to treat infections caused by critical pathogens spreading worldwide, Escherichia coli, Salmonella enterica serovar Typhimurium, and Klebsiella pneumoniae. Starting from a hit compound endowed with a nanomolar dissociation constant, we have rationally designed and synthesized a series of derivatives to be tested against S. Typhimurium OASS isoenzymes, StOASS-A and StOASS-B. All acidic derivatives have shown good activities in the nanomolar range against both OASS isoforms in vitro. Minimal Inhibitory Concentrations (MICs) were then evaluated, as well as compounds’ toxicity. The compounds endowed with good activity in vitro and low cytotoxicity have been challenged as a potential colistin adjuvant against pathogenic bacteria in vitro and the fractional inhibitory concentration (FIC) index has been calculated to define additive or synergistic effects. Finally, the target engagement inside the S. Typhimurium cells was confirmed by using a mutant strain in which the OASS enzymes were inactivated. Our results provide a robust proof of principle supporting OASS as a potential nonessential antibacterial target to develop a new class of adjuvants. more...

Infections caused by pathogens resistant to the available antimicrobial treatments represent nowadays a threat to global public health. Recently, it has been demonstrated that carbonic anhydrases (CAs) are essential for the growth of many pathogens and their inhibition leads to growth defects. Principal drawbacks in using CA inhibitors (CAIs) as antimicrobial agents are the side effects due to the lack of selectivity toward human CA isoforms. Herein we report a new class of CAIs, which preferentially interacts with microbial CA active sites over the human ones. The mechanism of action of these inhibitors was investigated against an important fungal pathogen, Cryptococcus neoformans, revealing that they are also able to inhibit CA in microbial cells growing in vitro. At our best knowledge, this is the first report on newly designed synthetic compounds selectively targeting β-CAs and provides a proof of concept of microbial CAs suitability as an antimicrobial drug target. more...