UNIQUE ENZYME TARGETS FOR GONOCOCCAL ANTIMETABOLITES

THE ABILITY OF NEISSERIA GONORRNOEAE TO METABOLIZE LACTATE DERIVED FROM HOST NEUTROPHILS HAS BEEN IMPIICITED IN A PATHOGENIC MECHANISM THAT FAVORS OXYGEN CONSUMPTION BY GONOCOCCI AND REDUCES THE ABILITY OF PHAGOCYTES TO PRODUCE SUPEROXIDE. A MEMBRANE-BOUND LACTATE DEHYDROGENASE (ILDH) AND SOLUBLE LACTATE DEHYDROGENASE (NLDH) PARTICIPATE IN LACTATE METABOLISM. SINGLE AND DOUBLE MUTANTS WILL BE USED TO ASSESS THE EFFECTS OF INHIBITORS OF ILDH AND/OR NLDH UPON GROWTH PHYSIOLOGY AND ENERGY METABOLISM. FEASIBILITY DEMONSTRATED BY THIS APPROACH WILL PROVIDE A RATIONALE FOR STRATEGIES TO ELUCIDATE THE GENE-ENZYME RELATIONSHIPS OF THIS SYSTEM TO ENHANCE INSIGHT INTO THE NATURE OF THE HOST-PATHOGEN INTERACTION. THE GENE SEQUENCES SHOULD, IN TURN, PROVIDE A MOLECULAR-GENETIC BASIS FOR EVENTUAL ATTEMPTS TO ABOLISH SELECTIVELY THE EXPRESSION OF THESE GENES. BY THE END OF THE PROPOSED GRANT PERIOD IT IS ANTICIPATED THAT A STRONG BASIS OF FEASIBILITY WILL BE ESTABLISHED (I) FOR DESIGN OF SELECTIVE INHIBITORS ACTING AT THE ENZYME LEVEL, (II) FOR DESIGN OF SELECTIVE ANTISENSE INHIBITORS ACTING AT THE LEVEL OF MRNA, AND (III) TO DEMONSTRATE DIRECTLY THE UTILITY OF THESE AS TOOLS TO DISRUPT THE PATHOGENIC STATE IN THE MOST APT MODEL SYSTEMS AVAILABLE.