![]() ![]() New, chemically distinct antibiotics are highly desirable as a strategy to circumvent antimicrobial resistance. New antimicrobials, especially those with novel mechanisms of action, are urgently needed however, most anti-infectives under development take advantage of existing antibiotic scaffolds with proven efficacy and established safety profiles ( Global Antimicrobial Resistance Hub, 2020 WHO (World Health Organisation), 2019b). aureus (MRSA) has been labeled a ‘serious threat’ by the Centers for Disease Control and Prevention ( CDC, 2019 Kourtis et al., 2019 Turner et al., 2019). Staphylococcus aureus is a devastating human pathogen. ![]() Some estimates have suggested that antimicrobial-resistant infections will cause as many as 10 million deaths annually by 2050 ( WHO (World Health Organisation), 2019a). In 2019, 2.8 million antibiotic-resistant infections occurred in the United States, resulting in 35,000 deaths ( CDC, 2019). ![]() These studies will enable structure-guided design of antistaphylococcal promoieties and expand the range of molecules to target staphylococcal pathogens.Īntimicrobial resistance presents a major challenge to public health ( Hsu, 2020 Antimicrobial resistance in the age of COVID-19, 2020). Finally, we establish the carboxy ester substrate specificities of human and mouse sera, ultimately identifying several promoieties likely to be serum esterase-resistant and microbially labile. Additionally, we determine the substrate specificities for FrmB and GloB and demonstrate the structural basis of these preferences. Here we identify the bacterial esterases, GloB and FrmB, that activate carboxy ester prodrugs in Staphylococcus aureus. While carboxy ester-based prodrug targeting is feasible, it has seen limited use in microbes as microbial esterase-specific promoieties have not been described. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, limiting their therapeutic potential. Prodrugging can mask problematic chemical features that prevent cellular uptake and may enable tissue-specific compound delivery. Carboxy ester prodrugs are widely employed to increase oral absorption and potency of phosphonate antibiotics. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |