Proton ATPases Biosynthesis

This limited arsenal of effective antifungal drugs highlights the urgent need for the development of novel therapeutic agents. Creative Biolabs has successfully launched an innovative antifungal drug discovery platform with customized services to discover antifungal drugs with a new mechanism of action different from those currently in use. Here is an introduction about proton ATPases biosynthesis which can be potential targets for antifungal drug discovery.

Why Need Antifungal Drug Discovery?

Opportunistic fungal infections have emerged as a major cause of morbidity and mortality in immunocompromised patients, including those with AIDS, hematological malignancies, and stem cell and organ transplant recipients. Collectively, invasive candidiasis, cryptococcal meningitis, invasive aspergillosis, and pneumocystis pneumonia are estimated to cause at least as many deaths worldwide as tuberculosis or malaria. However, the treatment of these life-threatening infections caused by eukaryotic pathogens still lags far behind that of infections due to other microorganisms, such as bacteria. Only four classes of drugs are currently available for treating invasive fungal infections: polyenes, azoles, pyrimidines, and echinocandins. This limited arsenal of effective drugs highlights the urgent need for the development of novel therapeutic agents, particularly in light of the emergence of drug-resistant strains, the growing number of immunocompromised patients to be treated, and the toxicity, high cost, and narrow activity spectra of the drugs currently available.

Proton ATPases as Potential Antifungal Targets

• V-ATPase

The importance of the V-ATPase in fungal physiology and virulence cannot be underestimated. Pathogenic fungi require optimum V-ATPase function for secretion of virulence factors, induction of stress response pathways, hyphal morphology and homeostasis of pH and other cations in order to successfully survive within and colonize the host. Recent evidence points to the V-ATPase as a novel downstream target of the azole class of antifungals that inhibit the biogenesis of ergosterol. Depletion of ergosterol from vacuolar membranes led to progressive alkalization of yeast vacuoles, loss of V-ATPase activity and growth inhibition that could be rescued by exogenous ergosterol feeding. Besides, other studies point to a critical role for sphingolipids, phospholipids, and cardiolipin in V-ATPase function. Thus, drugs that inhibit the V-ATPase directly, or indirectly by modulating the membrane milieu, can profoundly affect fungal viability and virulence.

Fig.1 Model of the V-type H⁺ ATPase expressed in a eukaryotic cell membrane. (Beyenbach, 2006)

• H⁺-ATPase

The plasma membrane H⁺-ATPase is an important new target for therapeutic intervention. The plasma membrane H⁺-ATPase is a predominant membrane protein that belongs to the P-type ATPase family of ion translocating plasma membrane H⁺-ATPase. It is an essential enzyme that plays a critical role in fungal cell physiology by maintaining the large transmembrane electrochemical proton gradient necessary for nutrient uptake and by helping to regulate intracellular pH. It is one of the few antifungal targets that have been shown to be essential by gene disruption. In addition to its role in cell growth, the plasma membrane H⁺-ATPase has been implicated in fungal pathogenicity through its effects on dimorphism, nutrient uptake, and medium acidification. These properties, along with the availability of numerous in vivo and in vitro screens that facilitate high throughput screening of compound libraries, make the plasma membrane H⁺-ATPase a highly desirable drug discovery target.

With the help of our well-established technologies and experienced scientists, Creative Biolabs offers antifungal drug discovery services with a new mechanism of action different from those currently in use. We provide very flexible options for each specific case. We are happy to make it accessible to all kinds of research and industrial customers. Besides, we are open to discussions. Please do not hesitate to contact us for more information.

Reference

1. Beyenbach, K.W.; Wieczorek, H. The V-type H⁺ ATPase: molecular structure and function, physiological roles and regulation. J Exp Biol. 2006, 209(Pt 4):577-89.

For Research Use Only.