Evaluation of MRSA virulence of structure-based drug against the lipoic acid salvage pathway using Caenorhabditis elegans

SCATTOLINI, A; GRAMMATOGLO, K; WINDSHÜGEL, B; JIRGENSONS, A; MANSILLA, MC

Congreso; Third Latin American Worm meeting; 2023

Methicillin resistant Staphylococcus aureus (MSRA) is an important human opportunistic pathogen responsible for a broad spectrum of diseases ranging from minor skin lesions to life-threatening postsurgical infections in humans. The versatility of S. aureus as a pathogen hinges on its release of virulence factors that compromise host immune defenses and on its capacity to adapt to host nutritional restriction by incorporating essential nutrients. Lipoic acid (LA) is a universally conserved sulfur-containing cofactor required for intermediary metabolism. S. aureus employs a “lipoyl-relay” pathway for de novo biosynthesis and salvage of this cofactor. It encodes two lipoate ligases, LplA1 and LplA2, a lipoyl-carrier protein (GcvH) and an amidotransferase, involved in LA rescue during infection. In this work, we performed a phenotypic screen of different molecules that were identified by a virtual screen against LplA2. We selected a compound, lpl-004, that caused a marked growth inhibition of the WT strain in minimal medium. This effect was less severe in ΔlplA1 or ΔlplA2 single mutants, while the growth of the double mutant ΔlplA1 ΔlplA2 was not affected. Using protein extracts of different bacterial mutants, we determined that lpl-004 would be bound to E2s. To test the effect of the treatment on S. aureus virulence we determined the lifespan of worms, using USA_300 grown in rich medium with and without the addition of lpl-004 as supplement. The observed increase in worm lifespan suggests that this compound could be useful for a combinatorial drug therapy against this pathogenic bacterium.