Evolutionary pathways towards β-lactam resistance in Haemophilus influenzae
Antimicrobial resistance is among the greatest global health threats, causing over 1.2 million deaths annually, with projections of 10 million by 2050 if not effectively addressed. Haemophilus influenzae, a WHO-designated Priority Pathogen and frequent cause of respiratory infections, increasingly shows resistance to β-lactam antibiotics such as ampicillin. Meanwhile, invasive infections including meningitis and sepsis are rising. This thesis investigates genetic mechanisms, evolutionary dynamics, and phenotypic effects of non-β-lactamase-mediated β-lactam resistance to improve diagnostics and treatment strategies. In β-lactamase-negative isolates, mutations in ftsI (encoding penicillin-binding protein 3, PBP3) are the main mechanism. A meta-analysis combined with phylogenomic and genome-wide association studies confirmed PBP3 substitution patterns linked to ampicillin and cefotaxime resistance and identified new candidate determinants, such as ompP2. Experimental evolution under selective pressure from ampicillin, cefotaxime, or ceftriaxone revealed ftsI and ompP2 mutations associated with decreased β-lactam susceptibility. Phenotypic heterogeneity was observed for specific ompP2 mutants. Furthermore, evolved mutants exhibited decreased bacterial fitness and collateral effects to other antibiotics. Finally, unstabe heteroresistance caused by a genomic inversion affecting ompP2 was identified, leading to transient ceftriaxone resistance that reverted under antibiotic-free conditions. This dynamic mechanism may evade standard diagnostics and contribute to therapeutic failure. Overall, this work provides new insights into the molecular and evolutionary basis of β-lactam resistance in H. influenzae, emphasizing the need for genome-based diagnostics and evolution-informed therapies.
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