Quinolones are some of the most frequently used, broad-spectrum antimicrobial agents. Resistance to these drugs has become a critical public health problem. Mutations in the drug target topoisomerases that result in drug resistance are well documented. In addition, overproduction of the multidrug efflux pump AcrAB has been reported to result in quinolone resistance in clinical isolates of E. coli. Our long-range goal is to determine how bacteria respond to exposure to quinolone agents and to use this knowledge to design more effective treatments. A goal of the present proposal is to identify the genetic alterations that lead to quinolone resistance in clinical E. coli strains and to determine the interrelationship between levels and frequency of quinolone resistance, the mutations, and other patient covariates. The central hypothesis is that following quinolone treatment, mutations conferring resistance occur additively, beginning with mutations in the topoisomerases and ultimately including overproduction of AcrAB and that the most resistant isolates contain additional mutations, including another multidrug efflux pump. Preliminary data support these hypotheses. Overproduction of any multidrug efflux pump has far reaching therapeutic consequences; antimicrobial agents from multiple different categories, in addition to the quinolones, would be ineffective against these bacteria. With the combined basic, clinical, statistical, genomic, and bioinformatic expertise of the investigators and the size of our patient population, we are uniquely poised to carry out the following specific aims: (1) Identify and categorize genetic alterations that cause quinolone resistance in clinical isolates. We will use high through-put methods to detect mutations in the genes that encode quinolone resistance. Statistical methods will be used to analyze potential interrelationships between the mutations. (2) Perform a prospective analysis of patient data. We will: (a) use the high-throughput methods developed in specific aim 1 to determine the genetic alterations occurring in E. coli isolated from patients hospitalized in the Texas Medical Center compared to isolates from various consortia around the world; (b) perform genome typing; (c) analyze these data with respect to demographic and clinical data for the patients to determine the probable causes of quinolone resistance. Until we have a better understanding of the mechanisms used by bacteria to cope with drug pressure, we cannot design better inhibitors or control antimicrobial resistant infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054830-02
Application #
6865481
Study Section
Special Emphasis Panel (ZRG1-SSS-K (10))
Program Officer
Korpela, Jukka K
Project Start
2004-03-15
Project End
2009-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
2
Fiscal Year
2005
Total Cost
$338,625
Indirect Cost
Name
Baylor College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Chou, Andrew; Nuila, Ricardo E; Franco, Luis M et al. (2016) Prevalence of hypervirulent Klebsiella pneumoniae-associated genes rmpA and magA in two tertiary hospitals in Houston, TX, USA. J Med Microbiol 65:1047-8
Irobalieva, Rossitza N; Fogg, Jonathan M; Catanese Jr, Daniel J et al. (2015) Structural diversity of supercoiled DNA. Nat Commun 6:8440
Pandey, Naresh; Nobles, Christopher L; Zechiedrich, Lynn et al. (2015) Combining random gene fission and rational gene fusion to discover near-infrared fluorescent protein fragments that report on protein-protein interactions. ACS Synth Biol 4:615-24
Carlson-Banning, Kimberly M; Chou, Andrew; Liu, Zhen et al. (2013) Toward repurposing ciclopirox as an antibiotic against drug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae. PLoS One 8:e69646
Swick, Michelle C; Evangelista, Michael A; Bodine, Truston J et al. (2013) Novel Conserved Genotypes Correspond to Antibiotic Resistance Phenotypes of E. coli Clinical Isolates. PLoS One 8:e65961
Singh, Renu; Swick, Michelle C; Ledesma, Kimberly R et al. (2012) Temporal interplay between efflux pumps and target mutations in development of antibiotic resistance in Escherichia coli. Antimicrob Agents Chemother 56:1680-5
Fogg, Jonathan M; Randall, Graham L; Pettitt, B Montgomery et al. (2012) Bullied no more: when and how DNA shoves proteins around. Q Rev Biophys 45:257-299
Catanese Jr, D J; Fogg, J M; Schrock 2nd, D E et al. (2012) Supercoiled Minivector DNA resists shear forces associated with gene therapy delivery. Gene Ther 19:94-100
Zechiedrich, Lynn (2012) Editorial comment to genome-wide transcriptome analysis of fluoroquinolone resistance in clinical isolates of Escherichia coli. Int J Urol 19:368-9
Zhao, N; Fogg, J M; Zechiedrich, L et al. (2011) Transfection of shRNA-encoding Minivector DNA of a few hundred base pairs to regulate gene expression in lymphoma cells. Gene Ther 18:220-4

Showing the most recent 10 out of 26 publications