new drug screening for chronic staph infection

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FEMS Immunol Med Microbiol. 2005 Jun 14; [Epub ahead of print]

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Identification of antimicrobial compounds active against

intracellular Staphylococcus aureus.

Malouin F, Brouillette E, ez A, Boyll BJ, Toth JL, Gage JL,

NE.

Centre d'Etude et de Valorisation de la Diversite Microbienne

(CEVDM), Departement de biologie, Faculte des sciences, Universite

de Sherbrooke, 2500 Boul. Universite, Sherbrooke, Que., Canada J1K

2R1.

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 0.12-32mugml(-1). One of the compounds (no. 8) showed

excellent activity against gram-positive (MICs 0.12mugml(-1)) and

gram-negative (MICs 0.12-4mugml(-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.

PMID: 15963705 [PubMed - as supplied by publisher]