Inhibitors of the sulfur assimilation pathway in bacterial pathogens as enhancers of antibiotic therapy.
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.
Barbara
B
Campanini
Marco
M
Pieroni
Samanta
S
Raboni
Stefano
S
Bettati
Roberto
R
Benoni
Chiara
C
Pecchini
Gabriele
G
Costantino
Dipartimento di Farmacia, Universita di Parma, Parco Area delle Scienze 23/A, 43124 Parma, Italy. andrea.mozzarelli@unipr.it.
Andrea
A
Mozzarelli
D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000378:metabolism*; D003545:Cysteine / Q000096:biosynthesis; D003547:Cysteine Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004352:Drug Resistance, Microbial; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013455:Sulfur / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D013455:Sulfur; D003547:Cysteine Synthase; D003545:Cysteine