Cell-division inhibitors: new insights for future antibiotics

• Published in: Nature reviews. Drug discovery Vol. 7; no. 4; pp. 324 - 338
• Main Authors: Lock, Rowena L., Harry, Elizabeth J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2008; Nature Publishing Group
• Subjects: Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer Research; Cell Cycle Proteins - antagonists & inhibitors; Cell division; Cell Division - drug effects; Drug Design; Drug resistance in microorganisms; Drug Resistance, Bacterial - drug effects; Humans; Medicinal Chemistry; Molecular Medicine; Pharmacology/Toxicology; Protein-protein interactions; review-article; Australia
• ISSN: 1474-1776; 1474-1784; 1474-1784; 1474-1776
• DOI: 10.1038/nrd2510

Key Points Bacterial cell division is an essential process that is not yet targeted by clinically approved antibacterials. However, it is an area of untapped potential, with antibacterial discovery efforts now well underway. The septation process is driven by at least 12 proteins that are recruited to the division site at midcell to form the division machinery known as the divisome. Several features of the bacterial cell-division proteins would make them good candidate antibacterial targets, including their essentiality, their conservation in a wide range of bacterial pathogens, and, for the membrane-bound proteins, the absence of homologues in eukaryotes, and their accessibility to inhibitory compounds by virtue of their external location. The earliest event in bacterial cell division is the recruitment of a tubulin-like protein, FtsZ, to the division site to form a Z ring. Many inhibitors of FtsZ have been identified using various approaches. Although all have been shown to inhibit FtsZ in vitro , and most have antibacterial activity, there is usually little or no evidence for their antibacterial activity being due to FtsZ inhibition. In this respect PC58538/PC170942 and viriditoxin are the most promising candidates. For many divisome proteins catalytic activity has not been identified, and it is the protein–protein interactions that play a key role in the assembly of the divisome and the division process. These interactions may prove attractive for targeting. The ZipA–FtsZ interaction has been the subject of antibacterial discovery with no promising leads as yet. Significant progress in the discovery and development of small-molecule inhibitors of protein–protein interactions has been made through a number of different strategies. A general strategy for targeting protein interfaces, which is likely to emerge in the future, could be used to inhibit the plethora of protein–protein interactions that occur in bacterial cell division, such as the well-conserved DivIB–DivIC–FtsL interaction. In recent years, the prevalence of multidrug-resistant bacteria has grown considerably, exacerbated by the limited discovery of novel classes of antibacterial agents. Here, Lock and Harry discuss the therapeutic potential of inhibiting bacterial cell division, highlight specific cell-division proteins representing likely antimicrobial targets, and review the recent progress in this exciting new field. The growing problem of antibiotic resistance has been exacerbated by the use of new drugs that are merely variants of older overused antibiotics. While it is naive to expect to restrain the spread of resistance without controlling antibacterial usage, the desperate need for drugs with novel targets has been recognized by health organizations, industry and academia alike. The wealth of knowledge available about the bacterial cell-division pathway has aided target-driven approaches to identify novel inhibitors. Here, we discuss the therapeutic potential of inhibiting bacterial cell division, and review the progress made in this exciting new area of antibacterial discovery.