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

E-ISSN： 1875-533x|22|2|187-213

ISSN： 0929-8673

Source： Current Medicinal Chemistry, Vol.22, Iss.2, 2014-12, pp. : 187-213

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Abstract

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