Platensimycin is a selective FabF inhibitor with potent antibiotic properties

TLDR: Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis through the selective targeting of β-ketoacyl-(acyl-carrier-protein (ACP) in the synthetic pathway of fatty acids.

Abstract: The worldwide spread of antibiotic resistance in pathogenic bacteria raises serious concerns that today's front-line antibiotics may become ineffective. So the discovery of a new class of compound with enormous potential as antibiotics is of great interest. Platensimycin is the first member of a novel class of natural products that selectively kills bacteria by inhibiting FabF/FabB proteins, a mechanism of action that is not used by any agents in clinical use. It is a potent antibiotic with broad-spectrum activity against Gram-positive bacteria, including clinically relevant drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. The future of platensimycins is considered in the News pages, and see the antimicrobials Web Focus on http://tinyurl.com/g8omx. A new class of antibiotics that targets bacterial lipid biosynthesis is isolated from Streptomyces platensis, and demonstrates potent in vitro and in vivo activity against Gram-positive bacteria — including methicillin-resistant Staphylococcus species. Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s1,2. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of β-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity.