Identification of antimicrobial compounds active against intracellular Staphylococcus aureus.
Small-colony variants (SCVs) of Staphylococcus aureus exhibit characteristics of bacteria that can penetrate mammalian cells and remain intracellular and innocuous for indefinite periods. These properties make SCVs a convenient tool that can be used to identify new antibacterial agents having activity against intracellular, quiescent bacteria. Agents active against SCVs could be useful in the treatment of chronic staphylococcal infections such as bovine mastitis. An hemB deletion mutant of S. aureus Newbould, a bovine mastitis isolate, having a stable, genetically defined SCV phenotype, was used in a screening program to identify compounds active against intracellular, gram-positive bacteria. Out of more than 260,000 compounds screened, nine compounds having the desired properties were identified. The range of MICs against gram-positive bacteria was < or = 0.12-32 microg ml-1. One of the compounds (no. 8) showed excellent activity against gram-positive (MICs < or = 0.12 microg ml-1) and gram-negative (MICs < or = 0.12-4 microg ml-1) bacteria. Each of the nine compounds demonstrated efficacy in a neutropenic mouse thigh infection model. Two compounds, including compound no. 8, reduced numbers of bacteria in a mouse mastitis model of infection. Application of a stepwise screening process has identified lead compounds that may be useful for treating persistent, intracellular infections.
Malouin
François
F
Centre d'Etude et de Valorisation de la Diversité Microbienne (CEVDM), Département de biologie, Faculté des sciences, Université de Sherbrooke, 2500 Boul. Université, Sherbrooke, Que., Canada. francois.malouin@usherbrooke.ca
Brouillette
Eric
E
Martinez
Alejandro
A
Boyll
Bobbi J
BJ
Toth
James L
JL
Gage
Jennifer L
JL
Allen
Norris E
NE
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D004195:Disease Models, Animal; D005260:Female; D005798:Genes, Bacterial; D066298:In Vitro Techniques; D008414:Mastitis, Bovine / Q000188:drug therapy / Q000382:microbiology; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009154:Mutation; D009503:Neutropenia / Q000188:drug therapy / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development
D000900:Anti-Bacterial Agents