Development of ABC transporter mutants of Aspergillus nidulans as innovative tools in drug discover

Alan C. Andrade, Ciska Braam and Maarten A

Author address: 

Lab. of Phytopathology, Wageningen, The Netherlands

Abstract: 

Antimicrobial resistance is a global problem that undoubtedly concerns modern society. The World Health Organization together with public health authorities worldwide, are already developing action plans with strategies and guidelines to combat this growing problem. Drug resistance is not a new phenomenon but has evolved since man began to use antibiotics. However, the development of new families of antimicrobials in previous decades made us believe that we could always remain ahead of the pathogens. Concern emerged in the late 1990s that resistance was accumulating without the discovery of new antimicrobials. A traditional way to discover these agents is broad-based whole cell screening with libraries of chemicals or natural extracts. A general problem facing this type of screening is that the ambient concentration of drugs is prone to be low. This problem is amplified by the function of multidrug pumps which occur in all living organisms. These pumps reduce the accumulation of drugs inside the test organism and will inevitably diminish the chances of the discovery of new drugs. Mutants of micro-organisms lacking multidrug-efflux pumps have significant potential for enhancement of the sensitivity to antimicrobial agents. Our major goal is to develop such mutants of Aspergillus nidulans. Using a combination of classical and molecular genetics, multiple knock-out mutants of ABC transporters (atr) genes from this fungus are being generated in different combinations. Results indicate that these mutants indeed display increased sensitivity to a broad range of toxicants. Hence, these mutants are usefull tools in screening programs of new lead compounds with antifungal activity.
2001

abstract No: 

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Full conference title: 

21st Fungal Genetics Conference
    • Fungal Genetics Conference 21st (2000)