A plasmid-encoded genetic switch orchestrates the bacterial virulence-fitness trade-off to drive antibiotic resistance dissemination

Abstract

ABSTRACT The global dissemination of multidrug-resistant plasmids poses a major threat to antimicrobial therapy. While these plasmids are known to carry antibiotic resistance genes, how they balance bacterial fitness and virulence to ensure their own persistence and dissemination remains unclear. Here, we identify a previously unannotated IncFII plasmid-encoded protein, which we name type 1 fimbrial repressor (T1FR). T1FR directly binds the fimS phase-variation switch, locking it in the “off” orientation to suppress type 1 fimbria (T1F) biogenesis, thereby attenuating bacterial adhesion, colonization, and pathogenicity. Concurrently, T1FR reprograms central carbon metabolism to offset the fitness cost of plasmid carriage, thereby enhancing plasmid transconjugative efficiency and host competitive fitness. This dual function is dynamically modulated by LtrA-mediated suppression of T1fr transcription, introducing plasticity into the virulence-fitness trade-off. Collectively, the LtrA-T1FR system orchestrates an evolutionary trade-off between plasmid fitness and host pathogenicity. Targeting the T1FR-T1F axis may offer a novel anti-adhesion therapeutic that avoids selection for antibiotic resistance. IMPORTANCE Bacterial resistance has become one of the most serious public health issues worldwide. The evolution and spread of drug-resistant plasmids represent one of the significant approaches for bacteria to acquire resistance, and drug-resistant bacteria often have a high mortality rate. However, the association and regulatory mechanism between antibiotic-resistant plasmids and bacterial virulence are currently unclear. The IncFII plasmid is considered an epidemic-resistant plasmid and plays a critical role in the widespread spread of carbapenem antibiotic resistance genes. This study identified a novel protein, T1FR type 1 fimbrial repressor), in IncFII plasmids and explored its regulatory mechanism by inhibiting the generation of host bacterial type 1 fimbriae, thereby weakening bacterial virulence and facilitating stable plasmid transmission. This study provides the scientific basis for understanding the correlation between bacterial resistance and virulence and promotes the scientific prevention and comprehensive management of bacterial infections. Bacterial resistance has become one of the most serious public health issues worldwide. The evolution and spread of drug-resistant plasmids represent one of the significant approaches for bacteria to acquire resistance, and drug-resistant bacteria often have a high mortality rate. However, the association and regulatory mechanism between antibiotic-resistant plasmids and bacterial virulence are currently unclear. The IncFII plasmid is considered an epidemic-resistant plasmid and plays a critical role in the widespread spread of carbapenem antibiotic resistance genes. This study identified a novel protein, T1FR type 1 fimbrial repressor), in IncFII plasmids and explored its regulatory mechanism by inhibiting the generation of host bacterial type 1 fimbriae, thereby weakening bacterial virulence and facilitating stable plasmid transmission. This study provides the scientific basis for understanding the correlation between bacterial resistance and virulence and promotes the scientific prevention and comprehensive management of bacterial infections.