Mutational signature analysis predicts bacterial hypermutation and multidrug resistance

Area of Science:

• Microbiology
• Genetics
• Clinical Medicine

Background:

• Loss of DNA mismatch repair (MMR) in bacteria can lead to hypermutation.
• Hypermutated bacteria are clinically associated with high rates of multidrug resistance (MDR).
• Pseudomonas aeruginosa is a clinically significant bacterium prone to developing resistance.

Purpose of the Study:

• To investigate the mutational signature of MMR-deficient Pseudomonas aeruginosa.
• To determine the mechanisms and speed of MDR acquisition in hypermutated P. aeruginosa.
• To evaluate strategies for preventing MDR and explore diagnostic applications of mutational analysis.

Main Methods:

• Induction of hypermutation in P. aeruginosa by MMR deficiency.
• Repeated exposure to various antibiotics to assess MDR acquisition.
• Analysis of bacterial mutational signatures.
• Testing rational drug combinations for MDR prevention.
• Screening clinical P. aeruginosa isolates for MMR deficiency and MDR status.

Main Results:

• Hypermutated MMR-deficient P. aeruginosa exhibits a unique mutational signature.
• Rapid MDR acquisition occurred upon repeated antibiotic exposure, independent of drug class.
• MDR arose through shared resistance mechanisms between sequential drugs.
• Rational drug combinations effectively prevented MDR development.
• A significant proportion of clinical P. aeruginosa isolates were MMR-deficient and already MDR or prone to resistance.

Conclusions:

• MMR deficiency drives rapid MDR acquisition in P. aeruginosa through common resistance pathways.
• Targeted antibiotic combinations can overcome hypermutator-driven resistance.
• Mutational signature analysis of clinical isolates is a valuable tool for predicting MDR and guiding treatment.