Comparative genomic analysis of clinical Candida glabrata isolates identifies multiple polymorphic loci that can improve existing multilocus sequence typing strategy.

Candida glabrata is the second leading cause of candidemia in many countries and is one of the most concerning yeast species of nosocomial importance due to its increasing rate of antifungal drug resistance and emerging multidrug-resistant isolates. Application of multilocus sequence typing (MLST) to clinical C. glabrata isolates revealed an association of certain sequence types (STs) with drug resistance and mortality. The current C. glabrata MLST scheme is based on single nucleotide polymorphisms (SNPs) at six loci and is therefore relatively laborious and costly. Furthermore, only a few high-quality C. glabrata reference genomes are available, limiting rapid analysis of clinical isolates by whole genome sequencing. In this study we provide long-read based assemblies for seven additional clinical strains belonging to three different STs and use this information to simplify the C. glabrata MLST scheme. Specifically, a comparison of these genomes identified highly polymorphic loci (HPL) defined by frequent insertions and deletions (indels), two of which proved to be highly resolutive for ST. When challenged with 53 additional isolates, a combination of TRP1 (a component of the current MLST scheme) with either of the two HPL fully recapitulated ST identification. Therefore, our comparative genomic analysis identified a new typing approach combining SNPs and indels and based on only two loci, thus significantly simplifying ST identification in C. glabrata. Because typing tools are instrumental in addressing numerous clinical and biological questions, our new MLST scheme can be used for high throughput typing of C. glabrata in clinical and research settings.

Drug metabolism in experimental tuberculosis: II. Modification of monooxygenase activities due to infection by the administration of isonicotinic acid hydrazide.

Isonicotinic acid hydrazide (INH) upon administration to tuberculous guinea pigs exhibited curative effect by bringing back the tissue weights to normal. The reduced hepatic content of cytochrome P450 and NADPH-cytochrome C reductase activity of tuberculous guinea-pigs was restored to normal by INH treatment. Also a similar effect of INH was observed in the case of aminopyrine-N-demethylase and benzphetamine-N-demethylase in the liver and lung of tuberculous guinea-pigs. But INH had little effect on the content of cytochrome b5 and NADH-cytochrome b5 reductase activity. The hepatic and pulmonary activities of glutathione-S-transferase exhibited a tendency to come back to normal while UDP-glucuronyl transferase was unaffected by INH administration to the infected animals. The results suggest that the treatment of tuberculous guinea-pigs with INH cause the normalisation of disturbed hepatic and pulmonary metabolism.