DOI: 10.1097/MOL.0b013e3282ff8630
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PMID: 18460926
Issn Print: 0957-9672
Publication Date: 2008/06/01
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Excerpt
Key articles are selected for comment by specialists and are highlighted in the following way:
• Papers considered to be of specialist interest
•• Papers considered to be of outstanding interest
A bibliographic listing follows each comment and selected papers are accompanied by an annotation in which the scope and context of the article are summarized briefly.
In a recent study, Liu and co-workers [1••] discovered a novel approach in antibacterial therapy to combat Staphylococcus aureus infections. Unexpectedly, a compound that had earlier been launched as a putative cholesterol-lowering agent owing to its inhibitory action on cholesterol biosynthesis turned out to block S. aureus virulence. This breakthrough comes at a time when multidrug-resistant bacteria have become a serious heath problem both in hospitals and in the general community, with methicillin-resistant S. aureus (MRSA) being one of the major threats [2]. The development of new antimicrobial agents has not been able to keep up with the rise in antimicrobial resistance, and the emergence of new drugs has been scarce. S. aureus derives its name from the golden color produced by the carotenoid pigment staphyloxanthin. This antioxidative pigment is an important virulence factor, and protects the bacteria against reactive oxygen species (ROS) that are produced by the host immune system [3]. The early steps of staphyloxanthin synthesis are remarkably similar to those of cholesterol synthesis in eukaryotes, a fact that may have major implications in the treatment of S. aureus infections.
The authors resolved the crystal structure of S. aureus dehydrosqualene synthase (CrtM). CrtM catalyses the committed step in staphyloxanthin biosynthesis: the condensation of two farnesyl diphosphate molecules resulting in presqualene diphosphate. In humans, presqualene diphosphate is a precursor for squalene that serves as an intermediate in cholesterol biosynthesis [4]. Human squalene synthase (SQS) inhibitors have therefore been proposed as cholesterol-lowering agents [5–8]. The crystal structure of human SQS has previously been resolved [9] and S. aureus CrtM was found to have a striking structural similarity to SQS. Importantly, this similarity was not evident from the primary structures of the proteins because their sequence homology was rather modest (30% identity and 36% similarity).
The authors have previously shown that S. aureus ΔCrtM mutants lack the bright yellow coloration of wild-type bacteria, and are susceptible to neutrophil killing by ROS [3]. This provides an elegant color-based screening assay for CrtM inhibitors. The investigators subsequently tested several SQS inhibitors to block the CrtM enzyme. Indeed, three inhibitors belonging to the phosphosulphonate group also inhibited CrtM, resulting in nonpigmented white bacteria. Crystallography was then used to resolve how these inhibitors bound to CrtM.
One of the inhibitors, BPH-652, has already been tested in humans for cholesterol lowering [10,11]. Liu and co-workers then analyzed the potential effect of this compound against staphylococcal infection by injecting mice intraperitoneally with S. aureus. This results in a systemic infection in which bacteria can be recovered after 72 h from the kidneys of the animals. In contrast, the S. aureus ΔCrtM only colonizes mucosal surfaces but fails to induce systemic infection. The authors found that administration of BPH-652 significantly reduced S. aureus bacterial counts in the kidneys of the treated mice as compared with the control group [1••], providing in-vivo evidence for the efficacy of this SQS inhibitor against S. aureus virulence. The way is thus paved for additional trials, including those with human subjects, and for hopefully further expanding the indications of cholesterol synthesis inhibitors beyond lipid disorders.
