Thymidylate Limitation Potentiates Cephalosporin Activity toward Enterococci via an Exopolysaccharide-Based Mechanism. ACS Chem Biol 2016 Jun 17;11(6):1561-8
Date
03/24/2016Pubmed ID
27008338Pubmed Central ID
PMC5238413DOI
10.1021/acschembio.5b01041Scopus ID
2-s2.0-84975251924 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
Multidrug resistant enterococci are major causes of nosocomial infections. Prior therapy with cephalosporins increases the risk of developing an enterococcal infection due to the intrinsic resistance of enterococci to these antibiotics. While progress has been made toward understanding the genetic and biochemical mechanisms of cephalosporin resistance, available data indicate that as-yet-unidentified resistance factors must exist. Here, we describe results of a screen to identify small molecules capable of sensitizing enterococci to broad-spectrum cephalosporins. We found that both Enterococcus faecalis and Enterococcus faecium were sensitized to broad and expanded-spectrum cephalosporins when thymidylate production was impaired, whether by direct inhibition of thymidylate synthase, or by limiting production of cofactors required for its activity. Cephalosporin potentiation is the result of altered exopolysaccharide production due to reduced dTDP-glucose synthesis. Hence, exopolysaccharide production is a previously undescribed contributor to the intrinsic cephalosporin resistance of enterococci and serves as a new target for antienterococcal therapeutics.
Author List
Hoff JS, Kristich CJAuthors
Jessica Hoff PhD Assistant Professor in the Pathology department at Medical College of WisconsinChristopher J. Kristich PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Anti-Bacterial AgentsCell Wall
Cephalosporins
Chloramphenicol
Drug Resistance, Multiple, Bacterial
Drug Synergism
Enterococcus faecalis
Enterococcus faecium
Fluorouracil
Folic Acid Antagonists
Glucose
Polysaccharides
Quinazolines
Tetrahydrofolate Dehydrogenase
Thymidine Monophosphate
Thymidylate Synthase
Thymine Nucleotides
Trimethoprim
