Inhibitors of the Sulfur Assimilation Pathway in Bacterial Pathogens as Enhancers of Antibiotic Therapy

Abstract

The rising emergence of antibiotic resistance urges the search for new strategies to defeat microorganisms that lead to persistent infections of the host. Tolerant to antibiotics, slowly replicating bacteria often cause latent and persistent infections that are the most challenging for pharmacological treatment. Persistence inside the host requires an extensive re-programming of the pathogen metabolic functions, due to the extremely hostile environment they face. Therefore, targeting key metabolic functions could result in better antibiotic treatments, shortened latency periods, and increased susceptibility to traditional antibiotics. Bacteria, differently from mammals, assimilate inorganic sulfur into cysteine, the precursor of a number of key metabolites including reducing agents, cofactors and membrane components. Inhibition of cysteine biosynthesis was proven to interfere heavily with the ability of pathogens to fight oxidative stress, to infect the host and to establish long-term infections. This review has the purpose of i) briefly summarizing the key structural and functional properties of transporters and enzymes involved in sulfur assimilation, ii) presenting biological evidence that supports the exploitation of this pathway for the identification of potential targets and, iii) highlighting intense efforts and advancements in the search of promising candidates for the development of novel compounds that enhance antibiotics therapy.

Cyclopropane-1,2-dicarboxylic acids as new tools for the biophysical investigation ofO-acetylserine sulfhydrylases by fluorimetric methods and saturation transfer difference (STD) NMR

“…These activities span from toxin activation in contact-dependent growth inhibition of uropathogenic E. coli strains 10 , to gene expression in B. subtilis 11 and the involvement of the enzyme in some pathologically-relevant processes as the formation of biofilm and swarming motility 19 . Considering that mammals synthesize cysteine via a metabolic pathway that involves enzymes different from those present in RSAP, inhibitors of bacterial cysteine biosynthesis might be able to potentiate antibiotic-based therapies 20 . Over the years, along with other groups 20,21 , we have investigated structural and functional properties of OASS isozymes with the aim of further characterizing the biological features of these proteins and to explore the possibility of their inhibition by small molecules.…”

“…Considering that mammals synthesize cysteine via a metabolic pathway that involves enzymes different from those present in RSAP, inhibitors of bacterial cysteine biosynthesis might be able to potentiate antibiotic-based therapies 20 . Over the years, along with other groups 20,21 , we have investigated structural and functional properties of OASS isozymes with the aim of further characterizing the biological features of these proteins and to explore the possibility of their inhibition by small molecules. The rational design of the first inhibitors was based on the structure of SAT, that physiologically inhibits OASS activity upon formation of the cysteine synthase bioenzyme complex 22,23 ; in particular, it was considered that the carboxylic moiety of Ile267 of SAT is essential for the interaction between the two proteins [22][23][24] .…”

Moonlighting O-acetylserine sulfhydrylase: New functions for an old protein

“…Because of the central role played by cysteine in bacterial physiology, it has been proposed that enzymes involved in its biosynthesis [40, 41], and OASS isozymes in particular [42, 43], could be exploited as targets for the development of new antibiotics. However, high levels of intracellular cysteine are potentially toxic to the cell.…”

Functional Site Discovery in a Sulfur Metabolism Enzyme by Using Directed Evolution

“…A promising new metabolic pathway for antimicrobial drugs is the sulphate assimilation pathway, [6] which is broadly present in bacteria, yeast, and fungi, essential for pathogen viability, and is not found in humans. In this pathway, inorganic sulphate is adenylated by the enzyme ATP sulphurylase, forming APS, which is subsequently reduced to sulphite and AMP.…”