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Antimicrobial Agents and Chemotherapy, February 2005, p. 741-748, Vol. 49, No. 2
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.2.741-748.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mutations in the Pneumocystis jirovecii DHPS Gene Confer Cross-Resistance to Sulfa Drugs

Peter Iliades,1* Steven R. Meshnick,2 and Ian G. Macreadie1

CSIRO, Health Sciences and Nutrition, Parkville, Victoria, Australia,1 Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina2

Received 20 August 2004/ Returned for modification 23 September 2004/ Accepted 4 October 2004

Pneumocystis jirovecii is a major opportunistic pathogen that causes Pneumocystis pneumonia (PCP) and results in a high degree of mortality in immunocompromised individuals. The drug of choice for PCP is typically sulfamethoxazole (SMX) or dapsone in conjunction with trimethoprim. Drug treatment failure and sulfa drug resistance have been implicated epidemiologically with point mutations in dihydropteroate synthase (DHPS) of P. jirovecii. P. jirovecii cannot be cultured in vitro; however, heterologous complementation of the P. jirovecii trifunctional folic acid synthesis (PjFAS) genes with an E. coli DHPS-disrupted strain was recently achieved. This enabled the evaluation of SMX resistance conferred by DHPS mutations. In this study, we sought to determine whether DHPS mutations conferred sulfa drug cross-resistance to 15 commonly available sulfa drugs. It was established that the presence of amino acid substitutions (T517A or P519S) in the DHPS domain of PjFAS led to cross-resistance against most sulfa drugs evaluated. The presence of both mutations led to increased sulfa drug resistance, suggesting cooperativity and the incremental evolution of sulfa drug resistance. Two sulfa drugs (sulfachloropyridazine [SCP] and sulfamethoxypyridazine [SMP]) that had a higher inhibitory potential than SMX were identified. In addition, SCP, SMP, and sulfadiazine (SDZ) were found to be capable of inhibiting the clinically observed drug-resistant mutants. We propose that SCP, SMP, and SDZ should be considered for clinical evaluation against PCP or for future development of novel sulfa drug compounds.

* Corresponding author. Mailing address: CSIRO Health Sciences and Nutrition, 343 Royal Parade, Parkville, Victoria 3052, Australia. Phone: (613) 9662 7259. Fax: (613) 9662 7266. E-mail: peter.iliades{at}csiro.au.

Antimicrobial Agents and Chemotherapy, February 2005, p. 741-748, Vol. 49, No. 2
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.2.741-748.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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