The impact of fatty acids on the antibacterial properties of N-thiolated β-lactams

Abstract

Bacterial fatty acid synthesis (FAS) is a potentially important, albeit controversial, target for antimicrobial therapy. Recent studies have suggested that the addition of exogenous fatty acids (FA) to growth media can circumvent the effects of FAS-targeting compounds on bacterial growth. Consequently, such agents may have limited in vivo applicability for the treatment of human disease, as free FAs are abundant within the body. Our group has previously developed N-thiolated β-lactams and found they function by interfering with FAS in select pathogenic bacteria, including MRSA. To determine if the FAS targeting activity of N-thiolated β-lactams can be abrogated by exogenous fatty acids, we performed MIC determinations for MRSA strains cultured with the fatty acids oleic acid and Tween 80. We find that, whilst the activity of the known FAS inhibitor triclosan is severely compromised by the addition of both oleic acid and Tween 80, exogenous FAs do not mitigate the antibacterial activity of N-thiolated β-lactams towards MRSA. Consequently, we propose that N-thiolated β-lactams are unique amongst FAS-inhibiting antimicrobials, as their effects are unimpeded by exogenous FAs.

Draft Genome Sequence of Strain CBD-635, a Methicillin-Resistant Staphylococcus aureus USA100 Isolate

“…The emergence of methicillin-resistant S. aureus (MRSA) strains that are resistant to last-resort antibiotics demonstrates the urgent need for new treatments and therapies to prevent and treat S. aureus infections. Previously, we have performed studies to identify novel antimicrobial compounds that could be used to treat strains of MRSA that are resistant to multiple classes of antibiotics (1–5). In these studies, we employed an extensively drug-resistant strain of MRSA (strain CBD-635) isolated from a sepsis patient at Tampa General Hospital.…”

“…Pulsed-field gel electrophoresis (PFGE) analysis demonstrated that CBD-635 is from the USA100 lineage and that the isolate is resistant to a variety of antimicrobial compounds, including methicillin, centhromycin, azithromycin, erythromycin, clindamycin, ampicillin, chloramphenicol, gentamicin, tetracycline, and ciprofloxacin, and demonstrates intermediary resistance to daptomycin, linezolid, and vancomycin. The use of strain CBD-635 in our drug discovery studies has facilitated the identification of promising new compounds to treat infections with multiply resistant bacteria (1–5). To gain insight into the mechanism of action of potential new antimicrobial agents, we have generated CBD-635 mutants that exhibit resistance to the new compounds (5).…”

“…The use of strain CBD-635 in our drug discovery studies has facilitated the identification of promising new compounds to treat infections with multiply resistant bacteria (1–5). To gain insight into the mechanism of action of potential new antimicrobial agents, we have generated CBD-635 mutants that exhibit resistance to the new compounds (5). Whole-genome sequencing will be employed to identify the mutation(s) that gives rise to resistance and therefore help elucidate the mechanism of action.…”