Pseudomonas Aeruginosa: Multidrug Resistance Mechanisms

Study Notes

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 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 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.

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 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.

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.

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.