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Antibiotic stops ‘ping-pong’ match

Nature volume 441, pages 293294 (18 May 2006) | Download Citation


As bacteria become resistant to existing drugs, there is a need for antibiotics with new modes of action. Such a compound has been found, and it works by binding to an intermediate in the catalytic cycle of its target.

Pathogenic bacteria have developed strains that are resistant to almost all antibiotics in use today. Particularly worrisome are infections by a large group of bacteria classified as being Gram-positive, such as staphylococci and enterococci, which cause pneumonia and other, often fatal, infections. The problem is highlighted by the emergence of multiply-drug-resistant strains of these organisms — so-called superbugs — that are resistant to vancomycin1, a drug widely recognized as the last line of defence in many Gram-positive bacterial infections. On page 358 of this issue2, Wang and colleagues report the discovery of a new antibiotic, platensimycin, that has potent antibacterial activity against these Gram-positive pathogens.

In the past 40 years, only two antibiotics representing new chemical classes have reached the clinic, namely linezolid (an oxazolidinone3) and daptomycin (a lipopeptide4). Most classes of antibiotic were discovered in the 1940s and 1950s, and are directed at a few specific aspects of bacterial physiology — mainly biosynthesis of the cell wall, and of DNA and proteins. Subsequent tweaking of these chemical scaffolds has produced most of today's antibiotics. It is believed that widespread drug resistance among bacterial pathogens is due to the limited choice of antibiotics that exploit a relatively narrow range of mechanisms. Wang and colleagues' report2 of a compound representing a novel class of antibiotic with activity against Gram-positive bacterial pathogens is thus particularly exciting, with the added bonus that platensimycin is effective against multiply-drug-resistant strains of staphylococci and enterococci.

The report reads like a textbook of modern antibacterial drug discovery, beginning with a screen of 250,000 extracts from drug-producing microorganisms. What follows is a series of elegant studies, spanning bacterial genetics, biochemistry, pharmacology and structural biology, and leading to the discovery of a small molecule derived from Streptomyces platensis that targets a seldom-exploited weakness in bacteria: fatty-acid biosynthesis. Fatty acids —organic acids with long hydrocarbon chains of between 8 and 18 carbon atoms — are the building-blocks of cell membranes and bacterial surfaces. They are produced through the repetitive action of biosynthetic machinery that elongates the chains two carbon atoms at a time. The target of platensimycin is a key enzyme component of this machinery: β-ketoacyl-ACP (acyl carrier protein) synthase, also known as FabF.

The FabF enzyme mediates a reaction that has a fascinating catalytic cycle (Fig. 1). The fatty acid to be elongated is first transferred from ACP to FabF, leaving the fatty acid bound to the enzyme through an active-site amino acid (cysteine), affording a transient acyl–enzyme intermediate5. The source of extender carbon atoms is a molecular fragment known as a malonyl group, which is attached to ACP. The malonyl–ACP substrate is bound by FabF, and then loses carbon dioxide to produce a reactive two-carbon unit. The reactive unit attacks the acyl–enzyme intermediate and yields an elongated product that is released from the enzyme. Enzymologists describe this series of reactions as ‘ping-pong’. This loose analogy refers to the way that the first substrate ‘pings’ into the active site and the first product ‘pongs’ out, leaving the enzyme altered, so that the second substrate does the same as the first, leading to a product known as β-ketoacyl-ACP (Fig 1). There is thus a strict order involving the addition of fatty acid–ACP and then malonyl–ACP.

Figure 1: The catalytic cycle of FabF for fatty-acid biosynthesis in bacteria.
Figure 1

a, The fatty-acid fragment (in blue; R represents a general hydrocarbon chain) is transferred from a sulphur atom on acyl carrier protein (ACP) to a sulphur atom on cysteine in the FabF active site. In response, the active site becomes more open. b, Malonyl–ACP substrate (in green) binds to the acyl–enzyme intermediate, and loses carbon dioxide. The fatty-acid fragment is transferred from the active site, adding to the remains of the malonyl–ACP substrate, and thus extending the chain. c, Wang et al.2 show that platensimycin inhibits the cycle by binding to the acyl–enzyme intermediate, preventing the addition of malonyl–ACP substrate — blocking fatty-acid biosynthesis, and so acting as an antibiotic.

Wang et al.2 provide an account of some terrific detective work that revealed that platensimycin binds only to the acyl–enzyme intermediate. Such intermediates are short-lived, typically with lifetimes of the order of milliseconds, and so are difficult to observe. To overcome this problem, the researchers created a mimic of the acyl–enzyme intermediate. They prepared a variant of the FabF enzyme in which the cysteine of the active site was replaced with the amino acid glutamine. The chemical group that forms the side chain of glutamine mimics a bound fatty acid. The variant enzyme bound platensimycin with high affinity, and a high-resolution crystal structure of the complex of variant FabF with the new antibiotic was obtained. The structure reveals that formation of the acyl–enzyme intermediate is accompanied by structural changes that open up the active site, permitting binding of platensimycin in such a way that it blocks the addition of malonyl–ACP.

Platensimycin is a significant new antibacterial compound with an extraordinary mechanism, but it is not the first antibiotic known to inhibit bacterial fatty-acid biosynthesis6,7. Isoniazid and triclosan are synthetic compounds that also target this pathway. Isoniazid has a clinical niche in treating tuberculosis in combination with other antibiotics, whereas triclosan has been widely used in soaps and plastics. In addition, cerulenin and thiolactomycin are natural products derived from fungi that target the same specific biosynthetic reaction as platensimycin in bacteria. That neither of these fungus-derived compounds has found a use in the clinic is testimony to the high standards required for a successful new antibiotic. Pharmaceutical companies have generally retreated from the field of antibacterial drugs, concentrating instead on chronic diseases with perceived product development and market advantages8. It is heartening, therefore, that platensimycin has been discovered and characterized by workers at Merck.

Wang et al. show that this antibiotic is effective in a mouse model of infection. The path ahead remains a long one that includes further preclinical study, and, if these studies are successful, extensive clinical trials for safety and efficacy in humans. Platensimycin is nevertheless the most potent inhibitor reported so far for FabF, and thus its discovery is an encouraging one.


  1. 1.

    et al. Science 302, 1569–1571 (2003).

  2. 2.

    et al. Nature 441, 358–361 (2006).

  3. 3.

    , & Curr. Drug Targets Infect. Disord. 1, 181–199 (2001).

  4. 4.

    & Expert Opin. Pharmacother. 5, 2321–2331 (2004).

  5. 5.

    , & J. Bacteriol. 185, 4136–4143 (2003).

  6. 6.

    & Annu. Rev. Microbiol. 55, 305–332 (2001).

  7. 7.

    , & Appl. Microbiol. Biotechnol.. 58, 695–703 (2002).

  8. 8.

    Curr. Opin. Microbiol. 6, 427–430 (2003).

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  1. Eric D. Brown is in the Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.

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