title: Perturbation of Staphylococcus aureus gene expression by the enoyl-acyl carrier protein reductase inhibitor AFN-1252.
abstract: This study examines the alteration in Staphylococcus aureus gene expression following treatment with the type 2 fatty acid synthesis inhibitor AFN-1252. An Affymetrix array study showed that AFN-1252 rapidly increased the expression of fatty acid synthetic genes and repressed the expression of virulence genes controlled by the SaeRS 2-component regulator in exponentially growing cells. AFN-1252 did not alter virulence mRNA levels in a saeR deletion strain or in strain Newman expressing a constitutively active SaeS kinase. AFN-1252 caused a more pronounced increase in fabH mRNA levels in cells entering stationary phase, whereas the depression of virulence factor transcription was attenuated. The effect of AFN-1252 on gene expression in vivo was determined using a mouse subcutaneous granuloma infection model. AFN-1252 was therapeutically effective, and the exposure (area under the concentration-time curve from 0 to 48 h [AUC(0-48)]) of AFN-1252 in the pouch fluid was comparable to the plasma levels in orally dosed animals. The inhibition of fatty acid biosynthesis by AFN-1252 in the infected pouches was signified by the substantial and sustained increase in fabH mRNA levels in pouch-associated bacteria, whereas depression of virulence factor mRNA levels in the AFN-1252-treated pouch bacteria was not as evident as it was in exponentially growing cells in vitro. The trends in fabH and virulence factor gene expression in the animal were similar to those in slower-growing bacteria in vitro. These data indicate that the effects of AFN-1252 on virulence factor gene expression depend on the physiological state of the bacteria.
authors: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Joshua B
authors: JB
authors: Parsons
authors: Maciej
authors: M
authors: Kukula
authors: Pamela
authors: P
authors: Jackson
authors: Mark
authors: M
authors: Pulse
authors: Jerry W
authors: JW
authors: Simecka
authors: David
authors: D
authors: Valtierra
authors: William J
authors: WJ
authors: Weiss
authors: Nachum
authors: N
authors: Kaplan
authors: Charles O
authors: CO
authors: Rock
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001572:Benzofurans / Q000493:pharmacokinetics / Q000494:pharmacology*; D050745:Enoyl-(Acyl-Carrier Protein) Reductase (NADPH, B-Specific) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D006099:Granuloma / Q000188:drug therapy / Q000382:microbiology; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011753:Pyrones / Q000493:pharmacokinetics / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C521531:API 1252; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001572:Benzofurans; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D011753:Pyrones; D037521:Virulence Factors; D050745:Enoyl-(Acyl-Carrier Protein) Reductase (NADPH, B-Specific); D000123:Acetyltransferases; D011494:Protein Kinases; C527351:SaeS protein, Staphylococcus aureus