4-Nitroquinoline-1-oxide: factors determining its mutagenicity in bacteria

In bacteria, 4-nitroquinoline-1-oxide (NQO) causes primarily mutations of the base-substitution type although frameshift mutations are also induced. The adducts formed are presumably recognized by error-prone DNA repair enzymes as evidenced by the much greater activity in plasmid pKM101-bearing tester strains. Although reduction of the nitro group appears to be required for mutagenic activity, this reduction is not catalyzed by the nitroreductase required for the demonstration of the mutagenicity in bacteria of other nitro-containing mutagens (nitrofurans, 2-nitronaphthalene, nitrofluorenes). The reduction of the nitro group appears to be catalyzed by a different nitroreductase. The mutagenicity of the non-carcinogenic 3-methyl-4-nitroquinoline-1-oxide (meNQO) may be related to this newly recognized nitroreductase. It is proposed, further, that the ultimate mutagenic intermediates derived from NQO and MeNQO differ.     

Impact of vaginal microbiome communities on HIV antiretroviral-based pre-exposure prophylaxis (PrEP) drug metabolism

Despite the efficacy of antiretroviral-based pre-exposure prophylactics (PrEP) in men who have sex with men, studies in women have produced widely varying outcomes. Recent evidence demonstrates that vaginal microbial communities are associated with increased HIV acquisition risk and may impact PrEP efficacy. Here, we investigate the mechanisms underlying how vaginal bacteria alter PrEP drug levels and impact HIV infection rates ex vivo. Using cervicovaginal lavages (CVLs) from women with or without bacterial vaginosis (BV), we identified microbial metabolism of PrEP drugs in BV samples through LC-MS/MS analysis of soluble drug levels and metabolite formation in dual T-cell cultures. CVL samples were assessed for microbiome analysis using sequencing of bacterial 16S rRNA genes. We also observed non-Lactobacillus bacteria that are associated with BV may potentially impact PrEP efficacy through increased HIV infection rates in co-cultures containing Lactobacillus or BV bacteria, PrEP drugs, CEM-GFP cells, and HIV-1_LAI virus. Finally, we used these data to develop a novel predictive mathematical simulation modeling system to predict these drug interactions for future trials. These studies demonstrate how dysbiotic vaginal microbiota may impact PrEP drugs and provides evidence linking vaginal bacteria to PrEP efficacy in women.