Bimodal Actions of a Naphthyridone/Aminopiperidine-Based Antibacterial That Targets Gyrase and Topoisomerase IV
Gyrase and topoisomerase IV are the targets of fluoroquinolone antibacterials. However, the rise in antimicrobial resistance has undermined the clinical use of this important drug class. Therefore, it is critical to identify new agents that maintain activity against fluoroquinolone-resistant strains...
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Veröffentlicht in: | Biochemistry (Easton) 2019-11, Vol.58 (44), p.4447-4455 |
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description | Gyrase and topoisomerase IV are the targets of fluoroquinolone antibacterials. However, the rise in antimicrobial resistance has undermined the clinical use of this important drug class. Therefore, it is critical to identify new agents that maintain activity against fluoroquinolone-resistant strains. One approach is to develop non-fluoroquinolone drugs that also target gyrase and topoisomerase IV but interact differently with the enzymes. This has led to the development of the “novel bacterial topoisomerase inhibitor” (NBTI) class of antibacterials. Despite the clinical potential of NBTIs, there is a relative paucity of data describing their mechanism of action against bacterial type II topoisomerases. Consequently, we characterized the activity of GSK126, a naphthyridone/aminopiperidine-based NBTI, against a variety of Gram-positive and Gram-negative bacterial type II topoisomerases, including gyrase from Mycobacterium tuberculosis and gyrase and topoisomerase IV from Bacillus anthracis and Escherichia coli. GSK126 enhanced single-stranded DNA cleavage and suppressed double-stranded cleavage mediated by these enzymes. It was also a potent inhibitor of gyrase-catalyzed DNA supercoiling and topoisomerase IV-catalyzed decatenation. Thus, GSK126 displays a similar bimodal mechanism of action across a variety of species. In contrast, GSK126 displayed a variable ability to overcome fluoroquinolone resistance mutations across these same species. Our results suggest that NBTIs elicit their antibacterial effects by two different mechanisms: inhibition of gyrase/topoisomerase IV catalytic activity or enhancement of enzyme-mediated DNA cleavage. Furthermore, the relative importance of these two mechanisms appears to differ from species to species. Therefore, we propose that the mechanistic basis for the antibacterial properties of NBTIs is bimodal in nature. |
doi_str_mv | 10.1021/acs.biochem.9b00805 |
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However, the rise in antimicrobial resistance has undermined the clinical use of this important drug class. Therefore, it is critical to identify new agents that maintain activity against fluoroquinolone-resistant strains. One approach is to develop non-fluoroquinolone drugs that also target gyrase and topoisomerase IV but interact differently with the enzymes. This has led to the development of the “novel bacterial topoisomerase inhibitor” (NBTI) class of antibacterials. Despite the clinical potential of NBTIs, there is a relative paucity of data describing their mechanism of action against bacterial type II topoisomerases. Consequently, we characterized the activity of GSK126, a naphthyridone/aminopiperidine-based NBTI, against a variety of Gram-positive and Gram-negative bacterial type II topoisomerases, including gyrase from Mycobacterium tuberculosis and gyrase and topoisomerase IV from Bacillus anthracis and Escherichia coli. GSK126 enhanced single-stranded DNA cleavage and suppressed double-stranded cleavage mediated by these enzymes. It was also a potent inhibitor of gyrase-catalyzed DNA supercoiling and topoisomerase IV-catalyzed decatenation. Thus, GSK126 displays a similar bimodal mechanism of action across a variety of species. In contrast, GSK126 displayed a variable ability to overcome fluoroquinolone resistance mutations across these same species. Our results suggest that NBTIs elicit their antibacterial effects by two different mechanisms: inhibition of gyrase/topoisomerase IV catalytic activity or enhancement of enzyme-mediated DNA cleavage. Furthermore, the relative importance of these two mechanisms appears to differ from species to species. 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However, the rise in antimicrobial resistance has undermined the clinical use of this important drug class. Therefore, it is critical to identify new agents that maintain activity against fluoroquinolone-resistant strains. One approach is to develop non-fluoroquinolone drugs that also target gyrase and topoisomerase IV but interact differently with the enzymes. This has led to the development of the “novel bacterial topoisomerase inhibitor” (NBTI) class of antibacterials. Despite the clinical potential of NBTIs, there is a relative paucity of data describing their mechanism of action against bacterial type II topoisomerases. Consequently, we characterized the activity of GSK126, a naphthyridone/aminopiperidine-based NBTI, against a variety of Gram-positive and Gram-negative bacterial type II topoisomerases, including gyrase from Mycobacterium tuberculosis and gyrase and topoisomerase IV from Bacillus anthracis and Escherichia coli. GSK126 enhanced single-stranded DNA cleavage and suppressed double-stranded cleavage mediated by these enzymes. It was also a potent inhibitor of gyrase-catalyzed DNA supercoiling and topoisomerase IV-catalyzed decatenation. Thus, GSK126 displays a similar bimodal mechanism of action across a variety of species. In contrast, GSK126 displayed a variable ability to overcome fluoroquinolone resistance mutations across these same species. Our results suggest that NBTIs elicit their antibacterial effects by two different mechanisms: inhibition of gyrase/topoisomerase IV catalytic activity or enhancement of enzyme-mediated DNA cleavage. Furthermore, the relative importance of these two mechanisms appears to differ from species to species. Therefore, we propose that the mechanistic basis for the antibacterial properties of NBTIs is bimodal in nature.</description><subject>Anti-Bacterial Agents - chemistry</subject><subject>Bacillus anthracis - enzymology</subject><subject>DNA Breaks, Double-Stranded - drug effects</subject><subject>DNA Cleavage - drug effects</subject><subject>DNA Gyrase - chemistry</subject><subject>DNA Topoisomerase IV - antagonists & inhibitors</subject><subject>DNA, Bacterial - drug effects</subject><subject>DNA, Single-Stranded - drug effects</subject><subject>Escherichia coli - enzymology</subject><subject>Indoles - chemistry</subject><subject>Mycobacterium tuberculosis - enzymology</subject><subject>Naphthyridines - chemistry</subject><subject>Piperidines - chemistry</subject><subject>Pyridones - chemistry</subject><subject>Topoisomerase II Inhibitors - chemistry</subject><issn>0006-2960</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kN1q3DAQRkVJaTZpn6AQ9ALeHVmSHd8ENiFNA6G92fZWjH4cK6wlIzmBfftou9uQ3vRKzOg738Ah5CuDJYOardDkpfbRDG5cdhrgEuQHsmCyhkp0nTwhCwBoqrpr4JSc5fxURgGt-EROOWtYy2W9IPHaj9Hilq7N7GPINPYU6Q-chnnYJW9jcKv16EOc_OTK7IOrrjE7S9dh9hrNXLYF3ww40w2mRzdnerdLJUIxWLqJU_Q5ju7P5v73Z_Kxx212X47vOfn17XZz8716-Hl3f7N-qFAIOVeWoTZdD8CxrjlvetDc9VbqVlvAHgzXTNrWNpdS1AKMxKYDa9uuMb3kwvJzcnXonZ716KxxYU64VVPyI6adiujVvz_BD-oxvqhWSJAcSgE_FJgUc06uf2MZqL1_Vfyro3919F-oi_dn35i_wktgdQjs6af4nEKx8N_KVztzl6w</recordid><startdate>20191105</startdate><enddate>20191105</enddate><creator>Gibson, Elizabeth G</creator><creator>Oviatt, Alexandria A</creator><creator>Cacho, Monica</creator><creator>Neuman, Keir C</creator><creator>Chan, Pan F</creator><creator>Osheroff, Neil</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0863-5671</orcidid><orcidid>https://orcid.org/0000-0001-6032-2528</orcidid><orcidid>https://orcid.org/0000-0002-2550-4884</orcidid><orcidid>https://orcid.org/0000-0002-4629-7642</orcidid></search><sort><creationdate>20191105</creationdate><title>Bimodal Actions of a Naphthyridone/Aminopiperidine-Based Antibacterial That Targets Gyrase and Topoisomerase IV</title><author>Gibson, Elizabeth G ; Oviatt, Alexandria A ; Cacho, Monica ; Neuman, Keir C ; Chan, Pan F ; Osheroff, Neil</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a445t-d1abc9f003a22336f0b3efd5b7bd0af0c3b15d7d6854240c5a690dd796cf534d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Anti-Bacterial Agents - chemistry</topic><topic>Bacillus anthracis - enzymology</topic><topic>DNA Breaks, Double-Stranded - drug effects</topic><topic>DNA Cleavage - drug effects</topic><topic>DNA Gyrase - chemistry</topic><topic>DNA Topoisomerase IV - antagonists & inhibitors</topic><topic>DNA, Bacterial - drug effects</topic><topic>DNA, Single-Stranded - drug effects</topic><topic>Escherichia coli - enzymology</topic><topic>Indoles - chemistry</topic><topic>Mycobacterium tuberculosis - enzymology</topic><topic>Naphthyridines - chemistry</topic><topic>Piperidines - chemistry</topic><topic>Pyridones - chemistry</topic><topic>Topoisomerase II Inhibitors - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gibson, Elizabeth G</creatorcontrib><creatorcontrib>Oviatt, Alexandria A</creatorcontrib><creatorcontrib>Cacho, Monica</creatorcontrib><creatorcontrib>Neuman, Keir C</creatorcontrib><creatorcontrib>Chan, Pan F</creatorcontrib><creatorcontrib>Osheroff, Neil</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Biochemistry (Easton)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gibson, Elizabeth G</au><au>Oviatt, Alexandria A</au><au>Cacho, Monica</au><au>Neuman, Keir C</au><au>Chan, Pan F</au><au>Osheroff, Neil</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bimodal Actions of a Naphthyridone/Aminopiperidine-Based Antibacterial That Targets Gyrase and Topoisomerase IV</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>2019-11-05</date><risdate>2019</risdate><volume>58</volume><issue>44</issue><spage>4447</spage><epage>4455</epage><pages>4447-4455</pages><issn>0006-2960</issn><eissn>1520-4995</eissn><abstract>Gyrase and topoisomerase IV are the targets of fluoroquinolone antibacterials. However, the rise in antimicrobial resistance has undermined the clinical use of this important drug class. Therefore, it is critical to identify new agents that maintain activity against fluoroquinolone-resistant strains. One approach is to develop non-fluoroquinolone drugs that also target gyrase and topoisomerase IV but interact differently with the enzymes. This has led to the development of the “novel bacterial topoisomerase inhibitor” (NBTI) class of antibacterials. Despite the clinical potential of NBTIs, there is a relative paucity of data describing their mechanism of action against bacterial type II topoisomerases. Consequently, we characterized the activity of GSK126, a naphthyridone/aminopiperidine-based NBTI, against a variety of Gram-positive and Gram-negative bacterial type II topoisomerases, including gyrase from Mycobacterium tuberculosis and gyrase and topoisomerase IV from Bacillus anthracis and Escherichia coli. GSK126 enhanced single-stranded DNA cleavage and suppressed double-stranded cleavage mediated by these enzymes. It was also a potent inhibitor of gyrase-catalyzed DNA supercoiling and topoisomerase IV-catalyzed decatenation. Thus, GSK126 displays a similar bimodal mechanism of action across a variety of species. In contrast, GSK126 displayed a variable ability to overcome fluoroquinolone resistance mutations across these same species. Our results suggest that NBTIs elicit their antibacterial effects by two different mechanisms: inhibition of gyrase/topoisomerase IV catalytic activity or enhancement of enzyme-mediated DNA cleavage. Furthermore, the relative importance of these two mechanisms appears to differ from species to species. Therefore, we propose that the mechanistic basis for the antibacterial properties of NBTIs is bimodal in nature.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>31617352</pmid><doi>10.1021/acs.biochem.9b00805</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-0863-5671</orcidid><orcidid>https://orcid.org/0000-0001-6032-2528</orcidid><orcidid>https://orcid.org/0000-0002-2550-4884</orcidid><orcidid>https://orcid.org/0000-0002-4629-7642</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Anti-Bacterial Agents - chemistry Bacillus anthracis - enzymology DNA Breaks, Double-Stranded - drug effects DNA Cleavage - drug effects DNA Gyrase - chemistry DNA Topoisomerase IV - antagonists & inhibitors DNA, Bacterial - drug effects DNA, Single-Stranded - drug effects Escherichia coli - enzymology Indoles - chemistry Mycobacterium tuberculosis - enzymology Naphthyridines - chemistry Piperidines - chemistry Pyridones - chemistry Topoisomerase II Inhibitors - chemistry |
title | Bimodal Actions of a Naphthyridone/Aminopiperidine-Based Antibacterial That Targets Gyrase and Topoisomerase IV |
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