The 2019 Garrod Lecture: MDR efflux in Gram-negative bacteria—how understanding resistance led to a new tool for drug discovery

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@article{635841f5179343569b8d1fd7379a7e08,
title = "The 2019 Garrod Lecture: MDR efflux in Gram-negative bacteria—how understanding resistance led to a new tool for drug discovery",
abstract = "The AcrAB-TolC MDR efflux system confers intrinsic MDR and overproduction confers clinically relevant resistance to some antibiotics active against Gram-negative bacteria. The system is made up of three components, namely AcrA, AcrB and TolC, otherwise known as the AcrAB-TolC tripartite system. Inactivation or deletion of a gene encoding one of the constituent proteins, or substitution of a single amino acid in the efflux pump component AcrB that results in loss of efflux function, confers increased antibiotic susceptibility. Clinically relevant resistance can be mediated by a mutation in acrB that changes the way AcrB substrates are transported. However, it is more common that resistant clinical and veterinary isolates overproduce the AcrAB-TolC MDR efflux system. This is due to mutations in genes such as marR and ramR that encode repressors of transcription factors (MarA and RamA, respectively) that when produced activate expression of the acrAB and tolC genes thereby increasing efflux. The Lon protease degrades MarA and RamA to return the level of efflux to that of the WT. Furthermore, the levels of AcrAB-TolC are regulated by CsrA. Studies with fluorescent reporters that report levels of acrAB and regulatory factors allowed the development of a new tool for discovering efflux inhibitors. Screens of the Prestwick Chemical Library and a large library from a collaborating pharmaceutical company have generated a number of candidate compounds for further research.",
keywords = "antibiotics, mutation, amino acids, veterinary technicians, endopeptidases, genes, gram-negative bacteria, libraries, transcription factor, transcriptional repression, proteolytic enzymes, antimicrobial susceptibility, drug discovery, pharmaceutical company, risk-adjusted mortality rate",
author = "Laura Piddock",
year = "2019",
month = nov,
doi = "10.1093/jac/dkz370",
language = "English",
volume = "74",
pages = "3128–3134",
journal = "Journal of Antimicrobial Chemotherapy",
issn = "0305-7453",
publisher = "Oxford University Press",
number = "11",

}

RIS

TY - JOUR

T1 - The 2019 Garrod Lecture

T2 - MDR efflux in Gram-negative bacteria—how understanding resistance led to a new tool for drug discovery

AU - Piddock, Laura

PY - 2019/11

Y1 - 2019/11

N2 - The AcrAB-TolC MDR efflux system confers intrinsic MDR and overproduction confers clinically relevant resistance to some antibiotics active against Gram-negative bacteria. The system is made up of three components, namely AcrA, AcrB and TolC, otherwise known as the AcrAB-TolC tripartite system. Inactivation or deletion of a gene encoding one of the constituent proteins, or substitution of a single amino acid in the efflux pump component AcrB that results in loss of efflux function, confers increased antibiotic susceptibility. Clinically relevant resistance can be mediated by a mutation in acrB that changes the way AcrB substrates are transported. However, it is more common that resistant clinical and veterinary isolates overproduce the AcrAB-TolC MDR efflux system. This is due to mutations in genes such as marR and ramR that encode repressors of transcription factors (MarA and RamA, respectively) that when produced activate expression of the acrAB and tolC genes thereby increasing efflux. The Lon protease degrades MarA and RamA to return the level of efflux to that of the WT. Furthermore, the levels of AcrAB-TolC are regulated by CsrA. Studies with fluorescent reporters that report levels of acrAB and regulatory factors allowed the development of a new tool for discovering efflux inhibitors. Screens of the Prestwick Chemical Library and a large library from a collaborating pharmaceutical company have generated a number of candidate compounds for further research.

AB - The AcrAB-TolC MDR efflux system confers intrinsic MDR and overproduction confers clinically relevant resistance to some antibiotics active against Gram-negative bacteria. The system is made up of three components, namely AcrA, AcrB and TolC, otherwise known as the AcrAB-TolC tripartite system. Inactivation or deletion of a gene encoding one of the constituent proteins, or substitution of a single amino acid in the efflux pump component AcrB that results in loss of efflux function, confers increased antibiotic susceptibility. Clinically relevant resistance can be mediated by a mutation in acrB that changes the way AcrB substrates are transported. However, it is more common that resistant clinical and veterinary isolates overproduce the AcrAB-TolC MDR efflux system. This is due to mutations in genes such as marR and ramR that encode repressors of transcription factors (MarA and RamA, respectively) that when produced activate expression of the acrAB and tolC genes thereby increasing efflux. The Lon protease degrades MarA and RamA to return the level of efflux to that of the WT. Furthermore, the levels of AcrAB-TolC are regulated by CsrA. Studies with fluorescent reporters that report levels of acrAB and regulatory factors allowed the development of a new tool for discovering efflux inhibitors. Screens of the Prestwick Chemical Library and a large library from a collaborating pharmaceutical company have generated a number of candidate compounds for further research.

KW - antibiotics

KW - mutation

KW - amino acids

KW - veterinary technicians

KW - endopeptidases

KW - genes

KW - gram-negative bacteria

KW - libraries

KW - transcription factor

KW - transcriptional repression

KW - proteolytic enzymes

KW - antimicrobial susceptibility

KW - drug discovery

KW - pharmaceutical company

KW - risk-adjusted mortality rate

UR - http://www.scopus.com/inward/record.url?scp=85073616434&partnerID=8YFLogxK

U2 - 10.1093/jac/dkz370

DO - 10.1093/jac/dkz370

M3 - Article

VL - 74

SP - 3128

EP - 3134

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

SN - 0305-7453

IS - 11

ER -