Proc Natl Acad Sci USA 2000, 97:6640–6645.CrossRefPubMed 27. Gust B, Challis GL, Fowler K, Kieser T, Chater KF: PCR-targeted Streptomyces

gene replacement identifies a protein Evofosfamide domain needed for biosynthesis of the sesquiterpene soil odor geosmin. Proc Natl Acad Sci USA 2003, 100:1541–1546.CrossRefPubMed Authors’ contributions YTC, TLL3, and SFT drafted the manuscript. YTC, and TLL designed and carried out the functional analyses. KMW, TLL1, YML, and HYS performed closure/finishing of the genome sequence. TLL3, IWH, JJY, MCL, YCL and JTW collected and classified the bacterial strains. YTC, TLL1, KMW, TLL3, and SFT analyzed the data. TLL3, JJY, MCL, YCL, IJH, JTW, and SFT contributed reagents/materials/analysis tools and participated in design and coordination of the study. YTC, KMW, HYS, and SFT performed annotation. All authors have read and approved the final manuscript.”
“Background Candida albicans causes systemic

infections, typically in immunocompromised patients, as well as mucosal infections such as oropharyngeal candidiasis (OPC) in HIV-infected patients and chronic vaginal infections [1, 2]. Azole antifungal drugs are the mainstay of management of such infections. However, with increased Ruxolitinib use of these agents, particularly fluconazole, treatment failures associated with the emergence of azole-resistant strains of C. SB-3CT albicans have occurred [3–6] This has been most evident in HIV/AIDS patients receiving long-term therapy for OPC [3, 7] The azoles bind to and inhibit the activity of lanosterol 14α-demethylase (Erg11p), a key enzyme in the fungal ergosterol biosynthesis pathway [8]. Several mechanisms of resistance to azoles have been described in C. albicans. These include increased expression of the drug efflux pump genes such as MDR1, CDR1 and CDR2 [3, 9–11], amino acid substitutions in the target enzyme Erg11p due to missense mutations in the ERG11 gene [3, 5, 10, 12–15] and possibly, overexpression of ERG11 [3, 16] Importantly in any one isolate, resistance may be due to a combination of mechanisms [3–5, 15].

To date, more than 60 amino acid substitutions have been described in Erg11p with at least 30 of these identified in azole-resistant isolates [5, 12, 14–17] The impact of individual substitutions, however, Akt inhibitor varies, and may differ between azoles. For example, substitutions such as Y132H, G450E, G464S, R467K and S405F appear to primarily impact on fluconazole and voriconazole, but not posaconazole, susceptibility [12, 13, 16, 17] The effect of substitutions can also be additive – strains with G129A and G464S substitutions display higher MICs azoles compared with those with the G129A substitution alone [18]. The contributions of yet other ERG11 mutations to resistance are uncertain [15, 19]. As most strains of C.