Type 3 Secretion System (T3SS) is a highly conserved virulence structure that plays an essential role in the pathogenesis of many Gram-negative pathogenic bacteria, including Pseudomonas aeruginosa. Exotoxin T (ExoT) is the only T3SS effector protein that is expressed in all T3SS-expressing P. aeruginosa strains. Here we show that T3SS recognition leads to a rapid phosphorylation cascade involving Abl / PKCδ / NLRC4, which results in NLRC4 inflammasome activation, culminating in inflammatory responses that limit P. aeruginosa infection in wounds. We further show that ExoT functions as the main anti-inflammatory agent for P. aeruginosa in that it blocks the phosphorylation cascade through Abl / PKCδ / NLRC4 by targeting CrkII, which we further demonstrate to be important for Abl transactivation and NLRC4 inflammasome activation in response to T3SS and P. aeruginosa infection.

Staphylococcus aureus is a leading cause of infection in the United States, and due to the rapid development of resistance, new antibiotics are constantly needed. trans-Translation is a particularly promising antibiotic target because it is conserved in many bacterial species, is critical for bacterial survival, and is unique among prokaryotes. We have investigated the potential of KKL-40, a small-molecule inhibitor of trans-translation, and find that it inhibits both methicillin-susceptible and methicillin-resistant strains of S. aureus. KKL-40 is also effective against Gram-positive pathogens, including a vancomycin-resistant strain of Enterococcus faecalis, Bacillus subtilis, and Streptococcus pyogenes, although its performance with Gram-negative pathogens is mixed. KKL-40 synergistically interacts with the human antimicrobial peptide LL-37, a member of the cathelicidin family, to inhibit S. aureus but not other antibiotics tested, including daptomycin, kanamycin, or erythromycin. KKL-40 is not cytotoxic to HeLa cells at concentrations that are 100-fold higher than the effective MIC. We also find that S. aureus develops minimal resistance to KKL-40 even after multiday passage at sublethal concentrations. Therefore, trans-translation inhibitors could be a particularly promising drug target against S. aureus, not only because of their ability to inhibit bacterial growth but also because of their potential to simultaneously render S. aureus more susceptible to host antimicrobial peptides.

Objectives The emergency medicine (EM) physician workforce is largely composed of white men. Despite recruitment efforts over the past decade, there has not been a significant increase of trainees with underrepresented racial and ethnic identities in EM (URM). Prior studies have focused on institutional strategies to improve diversity, equity, and inclusion (DEI) in EM residency recruitment but have been limited in describing URM trainees’ perspectives. We sought to assess URM trainees’ perspectives on DEI in the EM residency application and selection process. Methods This study was conducted at an urban academic medical center in the United States from November 2021 to March 2022. Junior residents were invited to participate in individual semistructured interviews. We used a combined deductive–inductive approach to categorize responses in predetermined areas of interest then elicit dominant themes within each category through consensus discussions. Thematic saturation was reached after eight interviews, indicating adequate sample size. Results Ten residents participated in semistructured interviews. All identified as racial or ethnic minorities. Three dominant themes emerged relating to authenticity, representation, and being treated as a learner first. Participants assessed the authenticity of a program's DEI efforts by evaluating the time frame and scope of DEI efforts. Participants reported a desire for representation of other URM colleagues in a residency program and training environment. While participants wanted their lived experience as URM trainees acknowledged, they were wary of being viewed solely through the lens of future DEI leaders rather than as learners first. Conclusions URM residents value multifaceted commitment to DEI efforts, representation, and being seen as learners first when assessing residency programs. Programs seeking to recruit URM residents should develop a department‐wide, multipronged, comprehensive DEI plan and showcase how their program will contribute to an applicant's professional development.