Bacterial infections remain a major public health challenge, worsened by the rapid rise of antimicrobial resistance. Among the most concerning pathogens are the ESKAPEE bacteria, which frequently cause hospital-acquired infections and are often resistant to multiple antibiotics. Antivirulence strategies offer promising alternatives to traditional treatments by disarming bacteria rather than killing them, potentially reducing the risk of resistance. However, progress in this field has been limited by the lack of reliable models to measure bacterial virulence and evaluate antivirulence compounds. In this study, we developed complementary models to better assess bacterial pathogenicity and treatment efficacy. We created an in vitro assay that mimics immune defenses and established insect infection models to compare virulence across pathogens and hosts. Using these systems, we tested NM102, a first-in-class antivirulence compound targeting bacterial DNA repair. NM102 reduced bacterial survival and infection severity, highlighting the potential of antivirulence approaches as innovative therapies against drug-resistant infections.

Proceedings of the National Academy of Sciences, Volume 123, Issue 40, October 2026. SignificanceQuorum sensing (QS) regulates diverse bacterial behaviors, and LuxR-type receptors are attractive targets for applications ranging from antivirulence strategies to synthetic biology and agriculture. Despite intense interest in developing ...

BNC exhibits opposing concentration-dependent effects: antivirulence at cytotoxic concentrations versus immunomodulatory and pro-regenerative at safe concentrations. Unmodified BNC is unsuitable as a...

Abstract. Clostridioides difficile (C. difficile) is a leading cause of antibiotic-associated diarrhea and colitis, with hypervirulent or resistant strains

<span><i>Staphylococcus aureus</i> exploits host extracellular matrix components to promote tissue invasion and dissemination. Here, we identify the serine-aspartate repeat protein C (SdrC) as a previously...

Polydatin attenuates MRSA pathogenicity by targeting ClpP associated virulence regulation rather than bacterial viability. These findings identify polydatin as a promising antivirulence candidate and...

Quorum sensing is often proposed as a target for antivirulence drug development against bacterial pathogens. Coagulase-negative staphylococci are leading causes of nosocomial blood infections and associated...

Quorum sensing (QS) inhibition has emerged as a promising target for directed drug design, providing an appealing strategy for developing antimicrobials, particularly against infections caused by dru...

Streptoclipamide A, a potent ClpP inhibitor (IC50 = 480 nM), was discovered by self-resistance-guided genome mining coupled with dual functional screening. It uniquely suppresses MRSA virulence toxin...

ost immune response in fighting the infection. Previous studies suggest that the US FDA–approved anti-inflammatory drug diflunisal inhibits Staphylococcus aureus (SA) α-toxin expression by its interac...

Author summary Acinetobacter baumannii causes infections that are difficult to treat due to high rates of antibiotic resistance, leading the World Health Organization and CDC to classify this pathogen...

Clostridioides difficile, a gram-positive anaerobe, is a leading cause of hospital-acquired diarrhea, responsible for 20,500 deaths from 462,100 infections in 2017 (1, 2). The primary risk factor for ...

Acinetobacter baumannii is a nosocomial Gram-negative pathogen of multi- and extensive-drug resistance phenotypes. In certain regions, multi-drug resistance rates can soar as high as 80-90%. Accordingly, reports by the World Health Organization and the Centers for Disease Control and Prevention unde …

<span><b>Introduction:</b> The persistent increase in multidrug-resistant pathogens has catalyzed the creation of novel strategies to address antivirulence and anti-infective elements. Such methodologies aim to diminish the selective pressure exerted on bacterial populations, decreasing the likelihood of</span> …

<span><b>Introduction:</b> The persistent increase in multidrug-resistant pathogens has catalyzed the creation of novel strategies to address antivirulence and anti-infective elements. Such methodologies aim to diminish the selective pressure exerted on bacterial populations, decreasing the likelihood of</span> …