Abstract
Carboxy ester prodrugs are widely employed to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can mask problematic chemical features that prevent cellular uptake and may enable tissue-specific compound delivery. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, limiting their therapeutic potential. While carboxy ester-based prodrug targeting is feasible, it has seen limited use in microbes as microbial esterase-specific promoieties have not been described. Here we identify the bacterial esterases, GloB and FrmB, that activate carboxy ester prodrugs in Staphylococcus aureus. Additionally, we determine the substrate specificities for FrmB and GloB and demonstrate the structural basis of these preferences. 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. These studies will enable structure-guided design of antistaphylococcal promoieties and expand the range of molecules to target staphylococcal pathogens.
Highlights
Antimicrobial resistance presents a major challenge to public health (Hsu, 2020)
Understanding the enzymatic and structural mechanisms of microbial prodrug activation will facilitate the development of microbe-specific prodrugs. 90 We recently described the staphylococcal enzyme, GloB, which facilitates activation of carboxy 91 ester prodrugs in S. schleiferi and S. pseudintermedius (Mikati et al, 2020)
Based on the hypothesized carboxy ester activation pathway, we predicted that the missing enzyme(s) might be either another carboxylesterase or a phosphodiesterase (Figure 1B)
Summary
In 2019, 2.8 million antibiotic-resistant infections occurred in the United States, resulting in 35,000 deaths (CDC, 2019). Some estimates have suggested that antimicrobial-resistant infections will cause as many as 10 million deaths annually by 2050 (World Health Organisation (WHO), 2019a). Methicillin-resistant S. 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). New antimicrobials, especially those with novel mechanisms of action, are urgently needed; most anti-infectives under development take advantage of existing antibiotic scaffolds with proven efficacy and established safety profiles (WHO, 2019b). Chemically distinct antibiotics are highly desirable as a strategy to circumvent antimicrobial resistance
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