The Enduring Menace of Antibiotic Resistance: Multidimensional Adaptation in High-Impact Clinical Pathogens and Prospects of Novel Interventions

This PhD thesis explores how high‑impact clinical pathogens adapt under sustained antibiotic pressure and examines complementary strategies to counteract their persistence. Focusing on Acinetobacter baumannii, Uropathogenic Escherichia coli and Streptococcus agalactiae, the work shows how resistance genes, virulence factors, and niche‑specific phenotypes interact to sustain survival in hospital and community settings, including the emergence of multidrug‑resistant and hypervirulent lineages. Within this framework, the thesis evaluates probiotic‑based and nanotechnology‑based approaches as antibiotic‑sparing options to limit colonization and infection by these priority pathogens. The thesis begins with an extensive review of antibiotic classes, major resistance mechanisms, and the epidemiology and persistence strategies of the three selected pathogens, alongside emerging non‑antibiotic interventions such as probiotics and nanoparticles. Subsequent project chapters dissect the genomic and phenotypic adaptation of A. baumannii and UPEC under clinical selective pressures, reveal the initial goblet-cell responses to A. baumannii in air-liquid interface cell models mimicking the airway epithelium, define the virulence–resistance landscape of colonizing and hypervirulent S. agalactiae isolates, and investigate the antagonistic potential of Lactobacillus spp. and serine‑based gemini nanoparticles as tools to reshape pathogen–host–microbiota interactions. Collectively, the findings reveal a coherent scenario in which resistance and virulence frequently co‑evolve, challenging conventional antibiotic‑centred management and underscoring the need for integrated ecological and physicochemical therapies. By combining detailed pathogen characterisation with proof‑of‑concept studies on probiotics and gemini‑based nanoparticles, this thesis contributes to a broader understanding of how alternative interventions might be employed to reduce maternal colonization, lower the spread of multidrug‑resistant lineages, and ultimately mitigate the burden of invasive bacterial disease.