pages 263-297

Recent Developments in Inhibitors of Bacterial Type IIA Topoisomerases

Chan P.F., Huang J., Bax B.D., Gwynn M.N.

Publication type: Book Chapter

Publication date: 2013-10-04

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DOI: 10.1002/9783527659685.ch11

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Abstract

Type II topoisomerases are a family of molecular machines, present in all cells, which choreograph a complex multistep catalytic cycle to transform DNA topology. Double‐stranded DNA cleavage, strand passage, and religation are linked to ATP hydrolysis, to supercoil, relax, decatenate, or unknot DNA. The DNA cleavage‐religation and ATPase domains present multiple sites for drug intervention, and are the targets of many classes of antibacterial and anticancer investigational and marketed drugs. The great variety of known inhibitors and their diverse mechanisms of action illustrate the molecular vulnerability of bacteria at these targets. However, it also highlights the challenge for drug developers, given that fluoroquinolones are still the only marketed antibacterial agents targeting type II topoisomerases. The structural basis of action of inhibitors acting at the DNA cleavage‐religation site, including fluoroquinolones and a novel class of antibacterial novel bacterial type II topoisomerase inhibitors (NBTIs), was only recently elucidated. This crystallographic platform, coming more than 40 years after the discovery of the quinolone antibacterials, provides new opportunities to explore the structural basis of action of other inhibitors, and to guide drug design and optimization to exploit this clinically validated target class.

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Citations by journals

	1 2
Biochemical Journal	Biochemical Journal, 2, 28.57% Biochemical Journal 2 publications, 28.57%
Antimicrobial Agents and Chemotherapy	Antimicrobial Agents and Chemotherapy, 1, 14.29% Antimicrobial Agents and Chemotherapy 1 publication, 14.29%
Acta Crystallographica Section F:Structural Biology Communications	Acta Crystallographica Section F:Structural Biology Communications, 1, 14.29% Acta Crystallographica Section F:Structural Biology Communications 1 publication, 14.29%
Nucleic Acids Research	Nucleic Acids Research, 1, 14.29% Nucleic Acids Research 1 publication, 14.29%
Proceedings of the National Academy of Sciences of the United States of America	Proceedings of the National Academy of Sciences of the United States of America, 1, 14.29% Proceedings of the National Academy of Sciences of the United States of America 1 publication, 14.29%
	1 2

Citations by publishers

	1 2
Portland Press	Portland Press, 2, 28.57% Portland Press 2 publications, 28.57%
American Society for Microbiology	American Society for Microbiology, 1, 14.29% American Society for Microbiology 1 publication, 14.29%
International Union of Crystallography (IUCr)	International Union of Crystallography (IUCr), 1, 14.29% International Union of Crystallography (IUCr) 1 publication, 14.29%
Oxford University Press	Oxford University Press, 1, 14.29% Oxford University Press 1 publication, 14.29%
Proceedings of the National Academy of Sciences (PNAS)	Proceedings of the National Academy of Sciences (PNAS), 1, 14.29% Proceedings of the National Academy of Sciences (PNAS) 1 publication, 14.29%
	1 2

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