N-Thiolated β-lactam antibacterials: Effects of the N-organothio substituent on anti-MRSA activity
Graphical abstract
A study on the structure–activity profiles of N-thiolated β-lactams are reported which demonstrate the importance of the N-organothio moiety on anti-MRSA activity.
Introduction
N-Thiolated β-lactams 1 are a new family of antibacterial agents active against Staphylococcus bacteria, including methicillin-resistant strains of Staphylococcus aureus (MRSA).1 Although these compounds exhibit antigrowth properties against other Staphylococcus species, including S. epidermidis, S. simulans, S. saprophyticus, and a few other genera such as Micrococcus luteus and Neisseria gonorrhoeae, a wide range of other Gram-positive and Gram-negative microbes appear to be unaffected.1b This observed selectivity for certain bacteria is rather interesting and undoubtedly relates to the mode of action, which has not yet been completely defined. Moreover, the ability of lactams 1 to retain their full antibacterial activity against drug-resistant microbes such as MRSA is attributable to the stability these compounds have toward bacterial penicillinases.1b The compounds are inert to hydrolytic degradation by these enzymes, a property highly desirable for a β-lactam drug, and do not inhibit the hydrolytic cleavage of penicillin G by β-lactamases. Additionally, the lactams possess promising anticancer properties, yet are not cytotoxic to normal mammalian (human fibroblast) cells at concentrations well beyond that needed to inhibit bacterial growth.2 Our studies also indicate that these N-thiolated lactams display different structure–activity profiles to those of traditional β-lactam antibacterials and exert their growth inhibitory effects in a manner which is unique to those of other β-lactams. For instance, the C3 and C4 ring substituents (R1–R4) have only a marginal effect on anti-MRSA activity, and neither relative nor absolute chirality at these two centers seems to significantly perturb activity.3These preliminary structure–activity studies also indicate that the N-organothio group may play a more important role, however, since replacement of the N-methylthio moiety for other N-substituents such as hydrogen, alkyl or alkoxy results in complete loss of bioactivity.
Section snippets
Preliminary model studies
A hypothetical model for the mode of action of these lactams, as depicted in Figure 1, serves as a starting point for these investigations. We have evidence that the antibacterial properties of these N-thiolated lactams come from the transfer of the organothio moiety onto its target with consequential loss of the N-protio lactam. We have been able to isolate this by-product by extraction of the cultured broth media with ethyl acetate. 1H NMR studies of the extract indicate the clean formation
Conclusions
The results of this study, in concert with our previously acquired data, support the empirical model presented in Figure 1 for the mode of antibacterial activity of N-thiolated β-lactams. While the lipophilic nature of the C3/C4 ring substituents may help the molecule transverse the lipid bilayer of the bacterial cell membrane, having too much lipophilicity in the organothio side chain appears to have a detrimental affect on antibacterial properties. This suggests that the organothio moiety
Experimental
All reagents were purchased from Sigma–Aldrich Chemical Company and used without further purification. Solvents were obtained from Fisher Scientific Company. Thin layer chromatography (TLC) was carried out using EM Reagent plates with a fluorescence indicator (SiO2-60, F-254). Products were purified by flash chromatography using J.T. Baker flash chromatography silica gel (40 mm). NMR spectra were recorded in CDCl3unless otherwise noted. 13C NMR spectra were proton broad-band decoupled.
Acknowledgment
Funding for this research was generously provided by the National Institutes of Health (R01 AI51351).
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