Beyond Antibiotics: Unveiling P. aeruginosa's Achilles' Heel

 

Pseudomonas aeruginosa is a common bacterium that causes opportunistic infections in humans and animals. It is innately antibiotic-tolerant, which, along with its highly adaptive metabolism and stress response systems, makes it a notoriously resistant pathogen. These characteristics are especially problematic in the current antibiotic resistance dilemma. P. aeruginosa can cause a variety of illnesses in susceptible people, including burn wound infections, sepsis, and pneumonia. The latter is particularly relevant in cystic fibrosis, when P. aeruginosa forms a persistent, stress-tolerant biofilm capable of evading the host immune system and tolerating medications. While antibiotics can help relieve symptoms, chronic, biofilm-associated P. aeruginosa infections are nearly impossible to eliminate. Phage treatment has been proposed as a backup or addition to biofilm-associated infections since it has various advantages over antibiotics in that specific domain. The biofilm matrix can impede antibiotic diffusion, making them less effective on less metabolically active cells. Biofilm can limit phage transport, however encoded depolymerases can counteract this by dispersing biofilm. While neither phage nor antibiotic can successfully kill dormant cells, the phage can become inactive as a pseudolysogen and then resume the lytic cycle when host metabolic activity returns.

Bacteriophage defensive mechanisms are common among bacteria, but they differ substantially in mechanism and specificity between species and strains. Current high-throughput discovery methodologies including phage DNA sequence-based restriction via restriction/modification (R/M) systems, as well as CRISPR-Cas acquired sequence-based restriction, anticipate phage defense loci based on their presence in "defense islands"—genomic locus containing numerous phage defense systems with different mechanisms. This allows for the discovery of novel defense mechanisms through their correlation with known ones. This has resulted in the identification of numerous phage defensive systems.

The researchers focused on three recently found genes in a laboratory-grown strain of P. aeruginosa. When they overexpressed these genes, they noticed a significant drop in biofilm. It is worth noting that the system affected by the genes is part of the P. aeruginosa core genome, which means it is present in all P. aeruginosa strains sequenced to date. When bacteria strains are subjected to stress, they can evolve independently and mutate rapidly. Patients infected with a P. aeruginosa strain may initially react well to antibiotic treatment but eventually become resistant when the bacterium evolves resistance during treatment. Strains mutate, but the common core genome remains unchanged.

The researchers activated the biofilm-reduction system by overexpressing genes. However, they discovered that stress on the cell wall naturally stimulates the mechanism. When battling infectious microorganisms, there are just a few targets to tackle. Targets located in both bacterial and human cells cannot be addressed because the antibiotics would also harm human cells. Bacterial and human cells share some targets, such as DNA replication and mechanisms that drive basic glucose metabolism or respiration in cells. Among the targets unique to bacteria are diverse protein functions, as well as the bacterial cell wall, which differs significantly from the human cell wall. 

REFERENCE:

Østergaard MZ, Nielsen FD, Meinfeldt MH, Kirkpatrick CL.0.The uncharacterized PA3040-3042 operon is part of the cell envelope stress response and a tobramycin resistance determinant in a clinical isolate of Pseudomonas aeruginosa. Microbiol Spectr0:e03875-23.https://doi.org/10.1128/spectrum.03875-23

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cover image: https://www.cdc.gov/pseudomonas-aeruginosa/media/images/P-Aeruginosa.jpg