Functional Linkage between Genes That Regulate Osmotic Stress Responses and Multidrug Resistance Transporters: Challenges and Opportunities for Antibiotic Discovery

Abstract

All cells need to protect themselves against the osmotic challenges of their environment by maintaining low permeability to ions across their cell membranes. This is a basic principle of cellular function, which is reflected in the interactions among ion transport and drug efflux genes that have arisen during cellular evolution. Thus, upon exposure to pore-forming antibiotics such as amphotericin B (AmB) or daptomycin (Dap), sensitive cells overexpress common resistance genes to protect themselves from added osmotic challenges. These genes share pathway interactions with the various types of multidrug resistance (MDR) transporter genes, which both preserve the native lipid membrane composition and at the same time eliminate disruptive hydrophobic molecules that partition excessively within the lipid bilayer. An increased understanding of the relationships between the genes (and their products) that regulate osmotic stress responses and MDR transporters will help to identify novel strategies and targets to overcome the current stalemate in drug discovery.

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

“…The broad substrate profile of the major multidrug exporters, the need for the drug to traverse the IM, and the OM permeability barrier clearly indicate key challenges in antibiotic development for Gram-negative bacteria (15,16,(943)(944)(945). The second requirement usually means that the drug must be made somewhat lipophilic, and this makes the drug susceptible to multidrug efflux.…”

The Role of Signaling via Aqueous Pore Formation in Resistance Responses to Amphotericin B

“…The increased hypersensitivity of the AmB-R strains to oxidative stress is particularly revealing because the osmoinducible Hog-1 genes that are required for the evolution of AmB-R yeast strains when exposed to increasing drug concentrations are known to be functionally connected to the defense against oxidative stress (5). Notably, in the AmB-R strains of C. albicans with deleted ERG3/ERG11 genes, a set of genes that are typically induced under iron starvation conditions are constitutively expressed, reflecting the fact that this stress is highly linked to ergosterol homeostasis (57).…”

“…Prevention of an increase in ion leakage leading to ATP depletion is important not only for AmB resistance but also for that developed by other amphiphilic drugs which partition into the membrane (5). In this respect, Purkait et al (74) have reported that AmB-R leishmanial strains displayed an increase in the level of expression of Mdr1, a member of the ATP-binding cassette (ABC) of protein transporters located in lipid rafts, which not only is involved in the efflux of amphiphilic compounds such as vin-blastine, puromycin, and doxorubicin (77) but also serves as a lipid translocase of broad specificity (78).…”

“…However, when the free monomeric forms predominate over large aggregates, AmB inserts spontaneously into ergosterol-containing membranes to form aqueous pores (4). The formation of aqueous pores by AmB has been linked to a diverse set of gradual responses leading to the emergence of resistance genes that protect the membrane against the disruptive effects of the antibiotic (5).…”

For Debate: May the Use of the Polyene Macrolide Natamycin as a Food Additive Foster Emergence of Polyene-Resistance in Candida Species?

“…Such sensing and cellular signalling mechanisms contribute as much to antifungal drug-resistance as alterations in the drug target [53,54]. Candida albicans, Saccharomyces cerevisiae, Aspergillus fumigatus and Trichophyton rubrum develop compensatory responses related to changes in the cell membrane caused by exposure to sub-inhibitory concentrations of Amphothericin B, Nystatin, Azoles and other drug classes [55][56][57][58][59][60][61][62][63][64][65][66][67]. Changes in gene expression triggered by exposure to sub-inhibitory drug concentrations affects genes involved in eg.…”