Some of the transporters existing in the membranes of pathogenic Candida species differ by its structure and activity from those of the host organism. These transporters thus may serve as targets for the development of new antifungal drugs that will affect yeast cells but not cells of the host.
Among more than 1400 known human pathogens, fungi and yeasts represent the second largest group - 22 % (after bacteria 38 %). Candidiasis is the most frequent fungal infection. Candida species are part of the normal human microflora, however these human commensals cause life-threatening infections in immunocompromised patients (due to AIDS, organ transplantations or cancer treatment) and can even kill human hosts in the case of treatment failure.
In 1929, Sir Alexander Fleming revealed to mankind a way of fighting against bacterial infections by the discovery of penicillin. Since that time, a wide collection of various antibiotics killing bacteria, including broad-spectrum ones, has been developed. The development of antifungal drugs has to overcome the obstacles of close evolutionary relationship between fungal and human cells. The animal (human) and yeast cells are eukaryotic, very similar to each other and simultaneously different from prokaryotic bacteria. Because of this evolutionary relationship, it is not easy to create drugs that would not damage the human host cells together with the fugal pathogen. In addition, in the course of evolution, the fungal cells have acquired a number of ways that enabled them to survive in adverse conditions and that help them now to gain resistance to antifungal agents.
Distribution of isolated Candida species from patients with candidemia (Pfaller et al., 2012):
|C. albicans||42.1 %|
|C. glabrata||26.7 %|
|C. parapsilosis||15.9 %|
|C. tropicalis||8.7 %|
|C. krusei||3.4 %|
|C. lusitaniae||1.1 %|
|C. dubliniensis||0.9 %|
|C. guilliermondii||0.4 %|
Candida albicans is able to undergo reversible morphological transitions between yeast (left) and filamentous forms (right) in response to external stimuli – temperature, pH, presence of nutrients or human hormones etc. Although yeast cells are disseminated more effectively, filamentous forms are better adapted to penetrate and damage host tissue.
Two directions are followed in our search for new antifungal drugs:
Potassium cations are crucial for many physiological processes (e.g. for negative charges compensations in macromolecules, for the regulation of intracellular pH, membrane potential or cell volume). Pathogenic yeast cells compete for K+ with the cells of their host; therefore Candida evolved efficient potassium transporters which belong to three groups: TRK, HAK and ACU. Whereas C. albicans has all three types of K+ uptake systems (Husekova et al., 2016; Elicharova et al., 2016), C. glabrata genome contains only one gene encoding a TRK-type transporter (Llopis-Torregrosa et al., 2016). To characterize the transport properties of these systems, we use a combination of two approaches:
Multidrug resistance mediated by membrane transporters is the main defense system of pathogenic microorganisms and cancer cells. Transporters actively remove antimicrobial or chemotherapeutic agents from the cells and thus prevent their intracellular accumulation in toxic levels. According to a source of energy, which is used to transport the substrate, the MDR transporters are divided into two main categories: