title: Thymidylate Limitation Potentiates Cephalosporin Activity toward Enterococci via an Exopolysaccharide-Based Mechanism.
abstract: 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.
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin , Milwaukee, Wisconsin, United States.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Hoff
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin , Milwaukee, Wisconsin, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kristich
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002473:Cell Wall / Q000187:drug effects; D002511:Cephalosporins / Q000494:pharmacology*; D002701:Chloramphenicol / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D004357:Drug Synergism; D013293:Enterococcus faecalis / Q000187:drug effects; D016984:Enterococcus faecium / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000031:analogs & derivatives* / Q000378:metabolism; D011134:Polysaccharides / Q000096:biosynthesis; D011799:Quinazolines / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013938:Thymidine Monophosphate / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D013942:Thymine Nucleotides / Q000378:metabolism*; D014295:Trimethoprim / Q000494:pharmacology
chemical_list: C000622572:5-(4-fluorophenoxy)quinazoline-2,4-diamine; C000622573:5-(4-methylphenyl)sulfanylquinazoline-2,4-diamine; D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D005493:Folic Acid Antagonists; D011134:Polysaccharides; D011799:Quinazolines; D013942:Thymine Nucleotides; C103522:deoxythymidine diphosphate-glucose; D013938:Thymidine Monophosphate; D002701:Chloramphenicol; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D005947:Glucose; D005472:Fluorouracil