Advances in Development of Novel Therapeutic Strategies against Multi-Drug Resistant Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa (P. aeruginosa) with multi-drug resistance (MDR) is a major cause of serious healthcare-associated infections, leading to high morbidity and mortality. This opportunistic pathogen is responsible for various infectious diseases, such as those seen in cystic fibrosis, ventilator-associated pneumonia, urinary tract infection, otitis externa, and burn and wound injuries. Due to its relatively large genome, P. aeruginosa has great diversity and can use various molecular mechanisms for antimicrobial resistance. For example, outer membrane permeability can contribute to antimicrobial resistance and is determined by lipopolysaccharide (LPS) and porin proteins. Recent findings on the regulatory interaction between peptidoglycan and LPS synthesis provide additional clues against pathogenic P. aeruginosa. This review focuses on recent advances in antimicrobial agents and inhibitors targeting LPS and porin proteins. In addition, we explore current and emerging treatment strategies for MDR P. aeruginosa, including phages, vaccines, nanoparticles, and their combinatorial therapies. Novel strategies and their corresponding therapeutic agents are urgently needed for combating MDR pathogens.

Keywords: Pseudomonas aeruginosa; lipopolysaccharide; multi-drug resistance; phage therapy; porin.

Figure 1

Mechanism of antimicrobial resistance related to LPS and porin in P. aeruginosa. Red dashed line arrows: LPS is transported from its synthesis site to the outer membrane. Yellow dashed line arrow: porins are channels that allow the entry of antibiotics. Red cross sign: narrow-channel porin is a barrier that blocks antibiotics from passing through the outer membrane. Red arrows: addition of a pEtN or L-Ara4N positively charged moiety to the lipid A of LPS. Red flat-headed arrows: inhibition of pathway. Red plus signs: upregulation of enzymatic activity; MurA stimulates LpxC activity, and novobiocin directly binds the ATPase LptB and increases the activity of the LPS transporter. MurA commits the first step of PG biosynthesis (long green arrow). LpxC commits the catalysis step of LPS biosynthesis (short green arrow).