Pseudomonas Aeruginosa: Multidrug Resistance Mechanisms

Pseudomonas Aeruginosa Pathogenesis

• Pseudomonas aeruginosa is a ubiquitous environmental bacterium that can establish opportunistic infections in plants, animals, and humans, including people with cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and non-CF bronchiectasis.
• It is the primary cause of Gram-negative nosocomial infections and lung infections in people with CF.

Adaptive Resistance Mechanisms

• Adaptive resistance mechanisms are transient and unstable, unlike mutational events, and become inactive upon removal of the stress factor.
• These mechanisms involve regulatory pathways, leading to altered gene expression, changes in protein production, or target alteration.
• Examples of adaptive resistance mechanisms include two-component signaling systems (TCSS), MexXY, and biofilm formation.

P. Aeruginosa Genome and Resistance

• P. aeruginosa has a large genome of 5.5-7 million base pairs with remarkable plasticity.
• The bacterium has 26 different types of porin, with OprF being the most abundant and implicated in various functions.
• OprF is present in two forms: a highly abundant two-domain closed channel and a single-domain open channel.

Antibiotic Uptake and Resistance

• Aminoglycosides diffuse through the outer membrane due to electrostatic interactions and undergo rapid energy-dependent accumulation into the cell.
• β-lactam antibiotics target trans-peptidases on the cytoplasmic membrane, while macrolides diffuse across the lipid bilayer due to their hydrophobic nature.
• Aminoglycoside resistance is achieved through mechanisms such as aminoglycoside-modifying enzymes, fusA1 mutation, 16S rRNA methylation, and MexXY-OprM upregulation.
• Fluoroquinolone resistance is achieved through mechanisms such as gyrA and parC mutation, leading to altered DNA gyrase and topoisomerase IV.
• β-lactamase production, including ESBLs and MBLs, may further enhance carbapenem, cephalosporin, and penicillin resistance.

Biofilm Formation and Antibiotic Resistance

• Biofilm structures are fundamental for P. aeruginosa infection of the CF lung and are also significant in patients with COPD, bronchiectasis, and chronic wounds.
• Airway mucins are found in abundance in people with CF, COPD, and bronchiectasis, and serve as a suitable attachment surface for P. aeruginosa biofilm formation.
• Biofilm structures are characterized by enhanced tolerance to antimicrobials, which can be further enhanced through the cooperation of MexAB-OprM and/or MexCD-OprJ.

Novel Therapies and Adjuvants

• Encapsulated antibiotics are more effective at preventing or eradicating biofilm formation than their free drug counterparts.
• Nitric oxide (NO) is a promising antibiotic adjuvant targeting biofilms, causing dispersal of biofilms and rendering the infection susceptible to antibiotics.

Global Antibiotic Resistance and Future Directions

• The global overuse and misuse of antibiotics have led to a profound increase in antimicrobial resistance.
• Antibiotic resistant infections have become more pervasive, according to global epidemiological antimicrobial resistance surveillance networks.
• Addressing antimicrobial resistance requires a One Health approach, involving human, animal, and environmental factors.

Explore the mechanisms of multidrug resistance in Pseudomonas aeruginosa, including the role of external stimuli and antibiotics. Learn about resistance-breaking therapies and adjuvant approaches.