Recent advances in bacterial topoisomerase inhibitors

Bradbury, Barton J.; Pucci, Michael J.

doi:10.1016/j.coph.2008.04.009

Cited by 95 publications

(58 citation statements)

References 74 publications

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“…Notably, several antimicrobials or other compounds, using new targets or mechanisms, were recently developed, and several have shown high in vitro activities against gonococcal isolates. These include novel inhibitors of protein synthesis, e.g., pleuromutilin BC-3781 (318,319) and the boron-containing inhibitor AN3365 (320,321); novel inhibitors of bacterial topoisomerases that target regions different from the fluoroquinolone-binding sites (322,323), such as VT12-008911 (324) and AZD0914 (323,325,326); FabI inhibitors, such as MUT056399 (327,328); noncytotoxic nanomaterials (329); inhibitors of efflux pumps, particularly coadministered with appropriate antimicrobials, that increase the susceptibility to certain antimicrobials, the innate host defense, and toxic metabolites (234,260,330); LpxC inhibitors (331); molecules mimicking host defensins; host defense peptides, such as LL-37 (multifunctional cathelicidin peptide) (332); and IL-12 NanoCap, which is a biodegradable sustained-release formulation of human interleukin 12 that aims to be a therapeutic vaccine against N. gonorrhoeae (TherapyX Inc.). Several of these novel antimicrobials or other types of compounds deserve further attention for their potential use as future treatments for gonorrhea.…”

Section: Future Perspectives For Treatmentmentioning

confidence: 99%

Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future

2014

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SUMMARY Neisseria gonorrhoeae is evolving into a superbug with resistance to previously and currently recommended antimicrobials for treatment of gonorrhea, which is a major public health concern globally. Given the global nature of gonorrhea, the high rate of usage of antimicrobials, suboptimal control and monitoring of antimicrobial resistance (AMR) and treatment failures, slow update of treatment guidelines in most geographical settings, and the extraordinary capacity of the gonococci to develop and retain AMR, it is likely that the global problem of gonococcal AMR will worsen in the foreseeable future and that the severe complications of gonorrhea will emerge as a silent epidemic. By understanding the evolution, emergence, and spread of AMR in N. gonorrhoeae , including its molecular and phenotypic mechanisms, resistance to antimicrobials used clinically can be anticipated, future methods for genetic testing for AMR might permit region-specific and tailor-made antimicrobial therapy, and the design of novel antimicrobials to circumvent the resistance problems can be undertaken more rationally. This review focuses on the history and evolution of gonorrhea treatment regimens and emerging resistance to them, on genetic and phenotypic determinants of gonococcal resistance to previously and currently recommended antimicrobials, including biological costs or benefits; and on crucial actions and future advances necessary to detect and treat resistant gonococcal strains and, ultimately, retain gonorrhea as a treatable infection.

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Section: Future Perspectives For Treatmentmentioning

confidence: 99%

Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future

2014

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“…Because of the attractive possibility of dual targeting, as demonstrated by the FQs, an area of active research has been the pursuit of inhibitors of the topoisomerases DNA gyrase and topoisomerase IV. This area has been reviewed recently (42,276). Interestingly, these topoisomerases themselves were identified relatively long after specific inhibitors targeting them were discovered empirically.…”

Section: Single Pharmacophore Multiple Targetsmentioning

confidence: 99%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,155

961

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SUMMARY The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort.

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“…Structural information on the covalent intermediates between members of the topoisomerase family and their DNA substrates is important not only in understanding how these enzymes manage the passage of DNA strands or double helices through one another, but also in the design of antimicrobial and antitumor agents that target the DNA topoisomerases. Compounds that result in the accumulation of the covalent complexes formed by type IIA and type IB topoisomerases, referred collectively as topoisomerase poisons, have been utilized extensively in antibacterial and anticancer therapy (3)(4)(5). All bacteria contain at least one type IA topoisomerase, usually topoisomerase I, along with at least one type IIA topoisomerase, usually DNA gyrase (6).…”

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confidence: 99%

Crystal structure of a covalent intermediate in DNA cleavage and rejoining by Escherichia coli DNA topoisomerase I

Zhang

Cheng

Tse-Dinh

2011

Proc. Natl. Acad. Sci. U.S.A.

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DNA topoisomerases control DNA topology by breaking and rejoining DNA strands via covalent complexes with cleaved DNA substrate as catalytic intermediates. Here we report the structure of Escherichia coli topoisomerase I catalytic domain (residues 2-695) in covalent complex with a cleaved single-stranded oligonucleotide substrate, refined to 2.3-Å resolution. The enzyme-substrate intermediate formed after strand cleavage was captured due to the presence of the D111N mutation. This structure of the covalent topoisomerase-DNA intermediate, previously elusive for type IA topoisomerases, shows distinct conformational changes from the structure of the enzyme without bound DNA and provides detailed understanding of the covalent catalysis required for strand cleavage to take place. The portion of cleaved DNA 5′ to the site of cleavage is anchored tightly with extensive noncovalent protein-DNA interactions as predicted by the "enzyme-bridged" model. Distortion of the scissile strand at the −4 position 5′ to the cleavage site allows specific selectivity of a cytosine base in the binding pocket. Many antibacterial and anticancer drugs initiate cell killing by trapping the covalent complexes formed by topoisomerases. We have demonstrated in previous mutagenesis studies that accumulation of the covalent complex of bacterial topoisomerase I is bactericidal. This structure of the covalent intermediate provides the basis for the design of novel antibiotics that can trap the enzyme after formation of the covalent complex.protein-DNA complex | topA | DNA relaxation | cytosine recognition A hallmark in reactions of all DNA topoisomerases is the formation of a covalent intermediate, in which an enzyme tyrosyl residue is covalently linked to a DNA phosphoryl group (1). These enzymes play a vital role in modulating DNA supercoiling and in untangling intracellular DNA during various cellular transactions (2). Structural information on the covalent intermediates between members of the topoisomerase family and their DNA substrates is important not only in understanding how these enzymes manage the passage of DNA strands or double helices through one another, but also in the design of antimicrobial and antitumor agents that target the DNA topoisomerases. Compounds that result in the accumulation of the covalent complexes formed by type IIA and type IB topoisomerases, referred collectively as topoisomerase poisons, have been utilized extensively in antibacterial and anticancer therapy (3-5). All bacteria contain at least one type IA topoisomerase, usually topoisomerase I, along with at least one type IIA topoisomerase, usually DNA gyrase (6). We have shown in previous genetic studies that trapping of bacterial topoisomerase I covalent complex intermediate due to mutations inhibiting DNA rejoining can result in rapid bacterial cell death (7, 8) in a mechanism involving reactive oxygen species (9). Bacterial topoisomerase I is thus a validated target that could be utilized for discovery of leads for antibacterial drugs that stabilize its c...

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Recent advances in bacterial topoisomerase inhibitors

Cited by 95 publications

References 74 publications

Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future

Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future

Challenges of Antibacterial Discovery

Crystal structure of a covalent intermediate in DNA cleavage and rejoining by Escherichia coli DNA topoisomerase I

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