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Cholesterol-Biosynthesis Inhibitor Stops Infection

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Cholesterol-Biosynthesis Inhibitor Stops Infection RESEA r CH HIGHLIGHTS Nature Reviews Drug Discovery | AOP, published online 14 March 2008; doi:10.1038/nrd2554 ANTIMICROBIALS Cholesterol-biosynthesis inhibitor stops infection The prevalence of multidrug-resistant They cloned and purified CrtM from bacterial strains has substantially S. aureus and revealed that despite increased over the past decade, and only modest sequence homology, the lack of new classes of antibiotics it had close structural similarity to has made the treatment of such human squalene synthase (SQS). infections increasingly challenging. This led to the hypothesis that inhibi- Now, writing in Science, Oldfield and tors of SQS that had already been colleagues demonstrate that com- developed as cholesterol-lowering pounds originally designed to lower drugs might also be active against cholesterol levels in humans could CrtM. have applications as effective To test their theory, they screened virulence-factor-based therapies a selection of eight SQS inhibitors against methicillin-resistant that were representative of the struc- Staphylococcus aureus (MRSA). tural diversity of this group of agents. bacterial counts in the kidney by 98%, S. aureus is the leading cause of Three of them — the phosphono­ achieving almost undetectable levels. many human infections, particularly sulphonates — inhibited CrtM Importantly, and consistent with those of the skin and soft tissues. and subsequent staphyloxanthin the low toxicity profile observed in Moreover, MRSA — a variation of formation. Further crystallographic previous clinical trials, BPH-652 had this bacterium that has evolved to analysis revealed the binding modes no effect on the growth of the various resist β-lactam antibiotics, includ- of these three compounds to CrtM. human cell lines tested. ing methicillin — is responsible for Next, the authors assessed the These data suggest that phosphono­ thousands of deaths each year. An antimicrobial potential of one of these sulphonate cholesterol-lowering important virulence factor in S. aureus phosphonosulphonates. BPH-652 agents provide a promising lead is the vivid golden carotenoid pigment was selected as the test compound, as for the development of a novel and staphyloxanthin, which acts as an it strongly inhibited staphyloxanthin safe anti-infective treatment against antioxidant to evade attack by reactive formation and had already progressed MRSA. Such virulence-factor-based oxygen species from the host immune into early human clinical trials as a approaches offer a new direction for system. Inhibition of staphyloxanthin cholesterol-lowering agent. therapies targeting multidrug-resistant biosynthesis is therefore an attractive Together with the production bacterial strains, and may theoretically potential therapeutic strategy to block of white S. aureus, which signifies reduce the selection pressure towards bacterial infection. the absence of the staphyloxanthin the emergence of resistance. Interestingly, earlier studies have antioxidant, BPH-652 dramati- Sarah Crunkhorn noted that the process of staphylo­ cally decreased S. aureus survival. xanthin production is strikingly Specifically, it demonstrated a 15-fold ORIGINAL RESEARCH PAPER Liu, C.-I. et al. similar to that of human cholesterol increased susceptibility to death of A cholesterol biosynthesis inhibitor blocks synthesis. Here, using X-ray crystal- S. aureus by hydrogen peroxide and Staphylococcus aureus virulence. Science 14 Feb 2008 (doi:10.1126/science.1153018) lography, the authors analysed the 4-fold decreased survival ability FURTHER READING Liu, G. et al. structure of an essential enzyme in freshly isolated human whole Staphylococcus aureus golden pigment impairs involved in the first crucial step blood. Furthermore, in a mouse neutrophil killing and promotes virulence through its antioxidant activity. J. Exp. Med. 202, of staphyloxanthin biosynthesis: model of systemic S. aureus infec- 209–215 (2005) dehydrosqualene synthase (CrtM). tion, BPH-652 treatment decreased © 2008 Nature Publishing Group .
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