Szilovics, Z. | Search bioRxiv

bioRxiv2026

A preclinical resistance framework discovers the virulence risks of antibiotics in development

Several new antibiotics target multidrug-resistant pathogens, yet resistance is still evaluated mainly by drug-susceptibility, leaving consequences for bacterial pathogenicity poorly understood. Here, we develop a framework integrating resistance evolution, genomic surveillance and host-pathogen phenotyping to classify antibiotics by resistance potential and pathogenic consequences. Applying this framework to Klebsiella pneumoniae identified functionally distinct antibiotic candidates associated with elevated virulence risk. Resistance evolution rapidly increased virulence through clinically-relevant mutations, without direct selection for pathogenicity. Despite distinct genetic routes, resistance converged on cell-envelope rewiring. A single resistance mutation increased epithelial adhesion, intracellular colonization, macrophage immune-evasion, and tissue persistence in murine infection models, transforming K. pneumoniae into a more invasive and cytotoxic pathogen. Risk-profile analysis revealed partial decoupling of resistance and pathogenicity, with some low-resistance antibiotics yielding highly-virulent populations. These findings establish resistance-driven virulence as an underappreciated translational hazard and call for incorporating host-pathogen interactions into resistance surveillance and preclinical antibiotic development.

microbiology↗

bioRxiv2023

Antibiotics of the future are prone to resistance in Gram-negative pathogens

Despite the ongoing development of new antibiotics, the future evolution of bacterial resistance may render them ineffective. We demonstrate that antibiotic candidates currently under development are as prone to resistance evolution in Gram-negative pathogens as clinically employed antibiotics. Resistance generally stems from both genomic mutations and the transfer of antibiotic resistance genes from microbiomes associated with humans, both factors carrying equal significance. The molecular mechanisms of resistance overlap with those found in commonly used antibiotics. Therefore, these mechanisms are already present in natural populations of pathogens, indicating that resistance can rapidly emerge through selection of pre-existing bacterial variants. However, certain combinations of antibiotics and bacterial strains are less prone to developing resistance, emphasizing the potential of narrow-spectrum antibacterial therapies that could remain effective. Our comprehensive framework allows for predicting future health risks associated with bacterial resistance to new antibiotics.

microbiology↗