bacillithiol and Staphylococcal-Infections

Bacillithiol is a low-molecular-weight thiol analogous to glutathione and is found in several Firmicutes, including Staphylococcus aureus. Since its discovery in 2009, bacillithiol has been a topic of interest because it has been found to contribute to resistance during oxidative stress and detoxification of electrophiles, such as the antibiotic fosfomycin, in S. aureus. The rapid increase in resistance of methicillin-resistant Staphylococcus aureus (MRSA) to available therapeutic agents is a great health concern, and many research efforts are focused on identifying new drugs and targets to combat this organism. This review describes the discovery of bacillithiol, studies that have elucidated the physiological roles of this molecule in S. aureus and other Bacilli, and the contribution of bacillithiol to S. aureus fitness during pathogenesis. Additionally, the bacillithiol biosynthesis pathway is evaluated as a novel drug target that can be utilized in combination with existing therapies to treat S. aureus infections.

Topics: Animals; Anti-Bacterial Agents; Cysteine; Glucosamine; Humans; Methicillin-Resistant Staphylococcus aureus; Phylogeny; Staphylococcal Infections; Staphylococcus aureus; Sulfhydryl Compounds

Disulfide analogs of the alcohol sobriety medication disulfiram (Antabuse®) were evaluated for antimicrobial activity. Structure-activity relationship analyses of MIC data obtained for methicillin-resistant Staphylococcus aureus (MRSA) and other pathogenic organisms revealed correlations between the lipophilicity and bulkiness of the substituents. Analogs conferring optimal anti-MRSA activity contained S-octyl disulfides and either N,N-dimethyl- or N-pyrrolidine dithiocarbamate substituents. Additional testing revealed that both disulfiram and its S-octyl derivative are capable of sensitizing S. aureus to the bactericidal effects of fosfomycin. Mechanistic studies established that the compounds decrease intracellular levels of the fosB cofactor bacillithiol through a thiol-disulfide exchange reaction. The increased fosfomycin susceptibility in S. aureus was thereby attributed to a depleted cellular bacillithiol pool available for inactivation by fosB.

Topics: Anti-Infective Agents; Bacterial Proteins; Cysteine; Disulfiram; Drug Resistance, Bacterial; Fosfomycin; Glucosamine; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Proto-Oncogene Proteins c-fos; Staphylococcal Infections; Sulfhydryl Compounds

The first step during bacillithiol (BSH) biosynthesis involves the formation of N-acetylglucosaminylmalate from UDP-N-acetylglucosamine and l-malate and is catalyzed by a GT4 class glycosyltransferase enzyme (BshA). Recombinant Staphylococcus aureus and Bacillus subtilis BshA were highly specific and active with l-malate but the former showed low activity with d-glyceric acid and the latter with d-malate. We show that BshA is inhibited by BSH and similarly that MshA (first enzyme of mycothiol biosynthesis) is inhibited by the final product MSH.

Topics: Antioxidants; Bacillaceae Infections; Bacillus subtilis; Bacterial Proteins; Cysteine; Enzyme Inhibitors; Glucosamine; Glycopeptides; Inositol; Kinetics; Malates; Models, Molecular; Molecular Targeted Therapy; Molecular Weight; N-Acetylglucosaminyltransferases; Protein Conformation; Recombinant Proteins; Staphylococcal Infections; Staphylococcus aureus; Substrate Specificity; Uridine Diphosphate N-Acetylglucosamine