Dataset Information

Long-term evolution of antibiotic tolerance in Pseudomonas aeruginosa lung infections.

ABSTRACT: Pathogenic bacteria respond to antibiotic pressure with the evolution of resistance but survival can also depend on their ability to tolerate antibiotic treatment, known as tolerance. While a variety of resistance mechanisms and underlying genetics are well characterized in vitro and in vivo, an understanding of the evolution of tolerance, and how it interacts with resistance in situ is lacking. We assayed for tolerance and resistance in isolates of Pseudomonas aeruginosa from chronic cystic fibrosis lung infections spanning up to 40 years of evolution, with 3 clinically relevant antibiotics: meropenem, ciprofloxacin, and tobramycin. We present evidence that tolerance is under positive selection in the lung and that it can act as an evolutionary stepping stone to resistance. However, by examining evolutionary patterns across multiple patients in different clone types, a key result is that the potential for an association between the evolution of resistance and tolerance is not inevitable, and difficult to predict.

SUBMITTER: Ghoul M

PROVIDER: S-EPMC10693005 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Long-term evolution of antibiotic tolerance in <i>Pseudomonas aeruginosa</i> lung infections.

Ghoul Melanie M Andersen Sandra B SB Marvig Rasmus L RL Johansen Helle K HK Jelsbak Lars L Molin Søren S Perron Gabriel G Griffin Ashleigh S AS

Evolution letters 20230920 6

Pathogenic bacteria respond to antibiotic pressure with the evolution of resistance but survival can also depend on their ability to tolerate antibiotic treatment, known as tolerance. While a variety of resistance mechanisms and underlying genetics are well characterized in vitro and in vivo, an understanding of the evolution of tolerance, and how it interacts with resistance in situ is lacking. We assayed for tolerance and resistance in isolates of <i>Pseudomonas aeruginosa</i> from chronic cys ...[more]

PMID: 38045720

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Project description:The widespread use of antibiotics promotes the evolution and dissemination of resistance and tolerance mechanisms. To assess the relevance of tolerance and its implications for resistance development, we used in vitro evolution and analyzed the inpatient microevolution of Pseudomonas aeruginosa, an important human pathogen causing acute and chronic infections. We show that the development of tolerance precedes and promotes the acquisition of resistance in vitro, and we present evidence that similar processes shape antibiotic exposure in human patients. Our data suggest that during chronic infections, P. aeruginosa first acquires moderate drug tolerance before following distinct evolutionary trajectories that lead to high-level multidrug tolerance or to antibiotic resistance. Our studies propose that the development of antibiotic tolerance predisposes bacteria for the acquisition of resistance at early stages of infection and that both mechanisms independently promote bacterial survival during antibiotic treatment at later stages of chronic infections.IMPORTANCE Over the past decades, pan-resistant strains of major bacterial pathogens have emerged and have rendered clinically available antibiotics ineffective, putting at risk many of the major achievements of modern medicine, including surgery, cancer therapy, and organ transplantation. A thorough understanding of processes leading to the development of antibiotic resistance in human patients is thus urgently needed. We show that drug tolerance, the ability of bacteria to survive prolonged exposure to bactericidal antibiotics, rapidly evolves in the opportunistic human pathogen Pseudomonas aeruginosa upon recurrent exposures to antibiotics. Our studies show that tolerance protects P. aeruginosa against different classes of antibiotics and that it generally precedes and promotes resistance development. The rapid evolution of tolerance during treatment regimens may thus act as a strong driving force to accelerate antibiotic resistance development. To successfully counter resistance, diagnostic measures and novel treatment strategies will need to incorporate the important role of antibiotic tolerance.

Project description:The Pseudomonas aeruginosa bacterium is a common pathogen of cystic fibrosis (CF) patients due to its ability to evolve resistance to antibiotics during treatments. While P. aeruginosa resistance evolution is well-characterized in monocultures, it is less well-understood in polymicrobial CF infections. Here, we investigated how exposure to ciprofloxacin, colistin, or tobramycin antibiotics, administered at sub-minimum inhibitory concentration (MIC) doses, both alone and in combination, shaped the tolerance evolution of P. aeruginosa (PAO1 lab and clinical CF LESB58 strains) in the absence and presence of a commonly co-occurring species, Stenotrophomonas maltophilia. The increases in antibiotic tolerances were primarily driven by the presence of that antibiotic in the treatment. We observed a reciprocal cross-tolerance between ciprofloxacin and tobramycin, and, when combined, the selected antibiotics increased the MICs for all of the antibiotics. Though the presence of S. maltophilia did not affect the tolerance or the MIC evolution, it drove P. aeruginosa into extinction more frequently in the presence of tobramycin due to its relatively greater innate tobramycin tolerance. In contrast, P. aeruginosa dominated and drove S. maltophilia extinct in most other treatments. Together, our findings suggest that besides driving high-level antibiotic tolerance evolution, sub-MIC antibiotic exposure can alter competitive bacterial interactions, leading to target pathogen extinctions in multispecies communities. IMPORTANCE Cystic fibrosis (CF) is a genetic condition that results in thick mucus secretions in the lungs that are susceptible to chronic bacterial infections. The bacterial pathogen Pseudomonas aeruginosa is often associated with morbidity in CF and is difficult to treat due to its high resistance to antibiotics. The resistance evolution of Pseudomonas aeruginosa is poorly understood in polymicrobial infections that are typical of CF. To study this, we exposed P. aeruginosa to sublethal concentrations of ciprofloxacin, colistin, or tobramycin antibiotics in the absence and presence of a commonly co-occurring CF species, Stenotrophomonas maltophilia. We found that low-level antibiotic concentrations selected for high-level antibiotic resistance. While P. aeruginosa dominated in most antibiotic treatments, S. maltophilia drove it into extinction in the presence of tobramycin due to an innately higher tobramycin resistance. Our findings suggest that, besides driving high-level antibiotic tolerance evolution, sublethal antibiotic exposure can magnify competition in bacterial communities, which can lead to target pathogen extinctions in multispecies communities.

Project description:Pseudomonas aeruginosa is an opportunistic human pathogen that usually causes difficult-to-treat infections due to its low intrinsic antibiotic susceptibility and outstanding capacity for becoming resistant to antibiotics. In addition, it has a remarkable metabolic versatility, being able to grow in different habitats, from natural niches to different and changing inpatient environments. Study of the environmental conditions that shape genetic and phenotypic changes of P. aeruginosa toward antibiotic resistance supposes a novelty, since experimental evolution assays are usually performed with well-defined antibiotics in regular laboratory growth media. Therefore, in this work we address the extent to which the nutrients' availability may constrain the evolution of antibiotic resistance. We determined that P. aeruginosa genetic trajectories toward resistance to tobramycin, ceftazidime, and ceftazidime-avibactam are different when evolving in laboratory rich medium, urine, or synthetic sputum. Furthermore, our study, linking genotype with phenotype, showed a clear impact of each analyzed environment on both the fitness and resistance level associated with particular resistance mutations. This indicates that the phenotype associated with specific resistance mutations is variable and dependent on the bacterial metabolic state in each particular habitat. Our results support that the design of evolution-based strategies to tackle P. aeruginosa infections should be based on robust patterns of evolution identified within each particular infection and body location. IMPORTANCE Predicting evolution toward antibiotic resistance (AR) and its associated trade-offs, such as collateral sensitivity, is important to design evolution-based strategies to tackle AR. However, the effect of nutrients' availability on such evolution, particularly those that can be found under in vivo infection conditions, has been barely addressed. We analyzed the evolutionary patterns of P. aeruginosa in the presence of antibiotics in different media, including urine and synthetic sputum, whose compositions are similar to the ones in infections, finding that AR evolution differs, depending on growth conditions. Furthermore, the representative mutants isolated under each condition tested render different AR levels and fitness costs, depending on nutrients' availability, supporting the idea that environmental constraints shape the phenotypes associated with specific AR mutations. Consequently, the selection of AR mutations that render similar phenotypes is environment dependent. The analysis of evolution patterns toward AR requires studying growth conditions mimicking those that bacteria face during in vivo evolution.

Dataset Information

Long-term evolution of antibiotic tolerance in Pseudomonas aeruginosa lung infections.

Publications

Long-term evolution of antibiotic tolerance in <i>Pseudomonas aeruginosa</i> lung infections.

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