Multidrug-resistant <i>Pseudomonas aeruginosa</i> : Pathogenesis, resistance mechanisms, and novel therapeutic strategies
Mohammed Salem Alharbi, Soha Abdallah Moursi, Ahmed Onayzan Alshammari, Rana Aboras, Ehab Rakha, Ashfaque Hossain, Sami Alshubrumi, Khaled Alnazha, Azharuddin Sajid Syed Khaja, Mohd Saleem
Abstract
Pseudomonas aeruginosa is a highly adaptable Gram-negative opportunistic pathogen and a major contributor to nosocomial infections, particularly in immunocompromised and critically ill patients. Its pathogenicity is mediated through an array of virulence determinants, including lipopolysaccharide (LPS), outer membrane proteins (OMPs), flagella, pili, and exopolysaccharides (alginate, Psl, Pel), which facilitate adhesion, immune evasion, and strong biofilm formation. The bacterium deploys an arsenal of secreted effectors such as exotoxins (ExoS, ExoT, ExoU, ExoY), pyocyanin, and elastases via specialized secretion systems (T1SS – T6SS) to disrupt host defenses and establish persistent infections. Resistance to antibiotics is multifactorial, encompassing restricted membrane permeability, efflux systems (e.g. MexAB-OprM), enzymatic inactivation (e.g. ESBLs, aminoglycoside-modifying enzymes), spontaneous mutations (e.g. gyrA, AmpC), and horizontal gene transfer. Biofilm-associated persister cells further complicate treatment by adopting metabolically dormant states. Innovative therapeutic approaches, including ceftolozane–tazobactam and small molecules with enhanced membrane permeability, are under investigation to circumvent resistance. Concurrently, vaccine development targeting key antigens such as LPS, flagella, T3SS proteins, and OMVs, along with nanoparticle-based platforms and monoclonal antibodies (e.g. IgY, DMAbs), has demonstrated potential in eliciting protective immunity. However, high antigenic variability and serotype diversity hinder broad efficacy. Future strategies must integrate Immunotherapeutics with antivirulence compounds targeting quorum sensing, iron acquisition, and biofilm disruption. A multidisciplinary approach involving translational research and clinical validation is imperative to combat multidrug-resistant P. aeruginosa and improve patient outcomes.