Quinidine drug resistance transporter knockout Candida cells modulate glucose transporter expression and accumulate metabolites leading to enhanced azole drug resistance.

ATP-binding cassette (ABC) and Major Facilitator Superfamily (MFS) transporters have been known to play an important role in the development of multidrug resistance (MDR) in various fungal species. While the importance of ABC transporters in MDR development is widely understood, MFS exporters have gotten little attention. The role of QDR (quinidine drug resistance) transporters (CaQDR1, CaQDR2, and CaQDR3), a subfamily of MFS, in conferring pathogenicity and virulence to Candida albicans is highlighted in this study. The transcriptome analysis of QDR knockout (QDRKO) strains versus wild-type (WT) strains of C. albicans reveals differential expression of some important virulence-associated gene categories. These include chitin and ß-glucan synthases, mannosyl transferases, vacuolar, ion transporters, acid phosphatase, and different sugar transporter (HGT8 and HGT9) encoding genes. Although some of the related phenotypic assays could not show any considerable differences in the growth of knockout strains under relevant stresses, however, we discovered elevated expression levels of different HGT genes in QDRKO strains, particularly under glucose limiting conditions as evidenced by the higher intracellular glucose accumulation levels. All the strains (QDRKOs and WT) followed a similar pattern in the accumulation of metabolite glycerol. Interestingly, QDRKO strains exhibit an enhanced azole drug resistance than the parental Candida strain, particularly at a low glucose concentration of the culture media. Our findings imply that deleting QDR genes (individually or collectively) alters cellular pathways, particularly those associated with glucose and glycerol accumulation. This possibly provides the cells with a mechanism to overcome stress and partially maintain the cellular pathogenicity/virulence in the absence of QDR MFS transporters.

Natural products and their semi-synthetic derivatives against antimicrobial-resistant human pathogenic bacteria and fungi.

Human infectious diseases caused by various microbial pathogens, in general, impact a large population of individuals every year. These microbial diseases that spread quickly remain to be a big issue in various health-related domains and to withstand the negative drug impacts, the antimicrobial-resistant pathogenic microbial organisms (pathogenic bacteria and pathogenic fungi) have developed a variety of resistance processes against many antimicrobial drug classes. During the COVID-19 outbreak, there seems to be an upsurge in drug and multidrug resistant-associated pathogenic microbial species. The preponderance of existing antimicrobials isn't completely effective, which limits their application in clinical settings. Several naturally occurring chemicals produced from bacteria, plants, animals, marine species, and other sources are now being studied for antimicrobial characteristics. These natural antimicrobial compounds extracted from different sources have been demonstrated to be effective against a variety of diseases, although plants remain the most abundant source. These compounds have shown promise in reducing the microbial diseases linked to the development of drug tolerance and resistance. This paper offers a detailed review of some of the most vital and promising natural compounds and their derivatives against various human infectious microbial organisms. The inhibitory action of different natural antimicrobial compounds, and their possible mechanism of antimicrobial action against a range of pathogenic fungal and bacterial organisms, is provided. The review will be useful in refining current antimicrobial (antifungal and antibacterial) medicines as well as establishing new treatment strategies to tackle the rising number of human bacterial and fungal-associated infections.