Mechanisms of drug resistance: quinolone resistance

Hooper, David C.; Jacoby, George A.

doi:10.1111/nyas.12830

Cited by 511 publications

(480 citation statements)

References 244 publications

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“…Unfortunately, despite this dual targeting, the rise of clinical resistance to FQs, most commonly by mutation in the conserved GyrA S83 and D87 amino acid residues (Escherichia coli numbering), has compromised the use of this important class of antibiotics, especially in infections caused by Gram-positive and -negative pathogens (13) and in MDR tuberculosis (14).…”

Section: Significancementioning

confidence: 99%

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

Chan

Germe

Bax

et al. 2017

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

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A paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase–DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development.

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Section: Significancementioning

confidence: 99%

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

Chan

Germe

Bax

et al. 2017

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

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“…Due to their effectiveness against both Gram-positive and Gram-negative bacteria, extensive use of fluoroquinolones has led to a rapid rise in resistance [229][230][231]. Development of resistance to quinolones entails multiple mechanisms [232,233]. The primary mechanism of quinolone resistance in Gram-negative bacteria is through mutations in target genes gyrA and gyrB [234][235][236][237].…”

Section: Fluoroquinolone Resistancementioning

confidence: 99%

Cell-wall recycling and synthesis in Escherichia coli and Pseudomonas aeruginosa – their role in the development of resistance

Dhar

Kumari

Balasubramanian

et al. 2018

Journal of Medical Microbiology

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The bacterial cell-wall that forms a protective layer over the inner membrane is called the murein sacculus -a tightly crosslinked peptidoglycan mesh unique to bacteria. Cell-wall synthesis and recycling are critical cellular processes essential for cell growth, elongation and division. Both de novo synthesis and recycling involve an array of enzymes across all cellular compartments, namely the outer membrane, periplasm, inner membrane and cytoplasm. Due to the exclusivity of peptidoglycan in the bacterial cell-wall, these players are the target of choice for many antibacterial agents. Our current understanding of cell-wall biochemistry and biogenesis in Gram-negative organisms stems mostly from studies of Escherichia coli. An incomplete knowledge on these processes exists for the opportunistic Gram-negative pathogen, Pseudomonas aeruginosa. In this review, cell-wall synthesis and recycling in the various cellular compartments are compared and contrasted between E. coli and P. aeruginosa. Despite the fact that there is a remarkable similarity of these processes between the two bacterial species, crucial differences alter their resistance to b-lactams, fluoroquinolones and aminoglycosides. One of the common mediators underlying resistance is the amp system whose mechanism of action is closely associated with the cell-wall recycling pathway. The activation of amp genes results in expression of AmpC blactamase through its cognate regulator AmpR which further regulates multi-drug resistance. In addition, other cell-wall recycling enzymes also contribute to antibiotic resistance. This comprehensive summary of the information should spawn new ideas on how to effectively target cell-wall processes to combat the growing resistance to existing antibiotics.

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“…However, the primary target enzyme, either DNA gyrase or topoisomerase IV, of FQs varies depending on the bacterial species. The preferential target of FQs in Gram-negative bacteria is DNA gyrase, whereas in Gram-positive microorganisms, topoisomerase IV is the primary target [58].…”

Section: The Current State Of Knowledge Of Quinolone Resistance Mechamentioning

confidence: 99%

“…The quinolones bind to these enzymes with DNA to form drug-enzyme-DNA complexes (known as a ternary complex) subsequently induces double-strand DNA breaks and blocks replication, therefore, results in damage to bacterial DNA and bacterial cell death [55][56][57][58]. However, the primary target enzyme, either DNA gyrase or topoisomerase IV, of FQs varies depending on the bacterial species.…”

Section: The Current State Of Knowledge Of Quinolone Resistance Mechamentioning

confidence: 99%

Quinolone Resistance in Non-typhoidal Salmonella

Kongsoi¹,

Nakajima²,

Suzuki³

2017

Current Topics in Salmonella and Salmonellosis

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Non-typhoidal Salmonella is the primary foodborne zoonotic agent of salmonellosis in many countries. Non-typhoidal Salmonella infections are transmited to humans primarily through consumption of contaminated foods from animal origin, whereas S. Typhi and Paratyphi infections are spread directly or indirectly by contact with an infected person. Quinolones exhibit potent antibacterial activity against Salmonella and are usually the irst choice of treatment for life-threatening salmonellosis due to multidrugresistant strains. However, by the early 1990s, quinolones have been approved for use in food-producing animals. The increased use of this group of antimicrobials in animal has led to the concomitant emergence of quinolone-resistant non-typhoidal Salmonella strains. However, in some countries, there are no legal provisions, which apply to veterinary drugs. This situation provides favorable conditions for spread and persistence of quinolone-resistant bacteria in food-producing animals. The objective of this chapter is to review the current regulatory controls for the use of quinolones in food-producing animals, its efect on development of quinolone resistance, and the potential impact on human and animal health. Moreover, this chapter reviews the current knowledge of quinolone resistance mechanisms and the future directions of research with particular atention to the strategies to control the emergence of quinolone-resistant Salmonella.

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Mechanisms of drug resistance: quinolone resistance

Cited by 511 publications

References 244 publications

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

Cell-wall recycling and synthesis in Escherichia coli and Pseudomonas aeruginosa – their role in the development of resistance

Quinolone Resistance in Non-typhoidal Salmonella

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