Biology subjects

Fidel, P. L.

Publications and source records attributed to Fidel, P. L..

2 recordsLinked to original sources

bioRxiv2024

A fungal metabolic regulator underlies infectious synergism during Candida albicans-Staphylococcus aureus intra-abdominal co-infection

Candida albicans and Staphylococcus aureus are two commonly associated pathogens that cause nosocomial infections with high morbidity and mortality. Our prior and current work using a murine model of polymicrobial intra-abdominal infection (IAI) uncovered synergistic lethality that was driven by Candida-induced upregulation of functional S. aureus -toxin leading to polymicrobial sepsis and organ damage. In order to determine the candidal effector(s) mediating enhanced virulence, an unbiased screen of C. albicans transcription factor mutants was undertaken and revealed that zcf13{Delta}/{Delta} failed to drive augmented -toxin or lethal synergism during co-infection. Using a combination of transcriptional and phenotypic profiling approaches, ZCF13 was shown to regulate genes involved in pentose metabolism, including RBK1 and HGT7 that contribute to fungal ribose catabolism and uptake, respectively. Subsequent experiments revealed that ribose inhibited the staphylococcal agr quorum sensing system and concomitantly repressed toxicity. Unlike wild-type C. albicans, zcf13{Delta}/{Delta} was unable to effectively utilize ribose during co-culture or co-infection leading to exogenous ribose accumulation and agr repression. Forced expression of RBK1 and HGT7 in the zcf13{Delta}/{Delta} mutant fully restored pathogenicity during co-infection. Collectively, our results detail the interwoven complexities of cross-kingdom interactions and highlight how intermicrobial metabolism impacts polymicrobial disease pathogenesis with devastating consequences for the host.

microbiology↗

bioRxiv2020

Mechanism of Action of a Prostaglandin E2 Receptor Antagonist with antimicrobial activity against Staphylococcus aureus

Our laboratory recently reported that the EP4 receptor antagonist, L-161,982, had direct growth-inhibitory effects on Staphylococcus aureus in vitro and in vivo, reducing microbial burden and providing significant protection against lethality in models of S. aureus monomicrobial and polymicrobial intra-abdominal infection. This antimicrobial activity was observed with both methicillin-sensitive and methicillin-resistant S. aureus (MRSA), as well as other Gram-positive bacteria. The antimicrobial activity of L-161,982 was independent of EP4 receptor inhibitory activity. In this study, we investigated the mechanism of action (MOA) of L-161,982, which contains a sulfonamide functional group. However, results demonstrate L-161,982 does not affect folate synthesis (sulfonamide MOA), oxidative stress, or membrane permeability. Instead, our results suggest that the inhibitor works via effects on inhibition of the electron transport chain (ETC). Similar to other ETC inhibitors, L-161,982 exposure results in a small colony size variant phenotype and inhibition of pigmentation, as well as significantly reduced hemolytic activity, and ATP production. In addition, L-161,982 potentiated the antimicrobial activity of another ETC inhibitor and inhibition was partially rescued by supplementation with nutrients required for ETC auxotrophs. Taken together, these findings demonstrate that L-161,982 exerts antimicrobial activity against MRSA via inhibition the ETC, representing a new member of a potentially novel antimicrobial drug class.

microbiology↗