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Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa.

ABSTRACT: Cheats are a pervasive threat to public goods production in natural and human communities, as they benefit from the commons without contributing to it. Although ecological antagonisms such as predation, parasitism, competition, and abiotic environmental stress play key roles in shaping population biology, it is unknown how such stresses generally affect the ability of cheats to undermine cooperation. We used theory and experiments to address this question in the pathogenic bacterium, Pseudomonas aeruginosa Although public goods producers were selected against in all populations, our competition experiments showed that antibiotics significantly increased the advantage of nonproducers. Moreover, the dominance of nonproducers in mixed cultures was associated with higher resistance to antibiotics than in either monoculture. Mathematical modeling indicates that accentuated costs to producer phenotypes underlie the observed patterns. Mathematical analysis further shows how these patterns should generalize to other taxa with public goods behaviors. Our findings suggest that explaining the maintenance of cooperative public goods behaviors in certain natural systems will be more challenging than previously thought. Our results also have specific implications for the control of pathogenic bacteria using antibiotics and for understanding natural bacterial ecosystems, where subinhibitory concentrations of antimicrobials frequently occur.

SUBMITTER: Vasse M

PROVIDER: S-EPMC5255613 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa.

Vasse Marie M Noble Robert J RJ Akhmetzhanov Andrei R AR Torres-Barceló Clara C Gurney James J Benateau Simon S Gougat-Barbera Claire C Kaltz Oliver O Hochberg Michael E ME

Proceedings of the National Academy of Sciences of the United States of America 20170103 3

Cheats are a pervasive threat to public goods production in natural and human communities, as they benefit from the commons without contributing to it. Although ecological antagonisms such as predation, parasitism, competition, and abiotic environmental stress play key roles in shaping population biology, it is unknown how such stresses generally affect the ability of cheats to undermine cooperation. We used theory and experiments to address this question in the pathogenic bacterium, Pseudomonas ...[more]

PMID: 28049833

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Project description:With the rising development of bacterial resistance the search for new medical treatments beyond conventional antimicrobials has become a key aim of public health research. Possible innovative strategies include the inhibition of bacterial virulence. However, consideration must be given to the evolutionary and environmental consequences of such new interventions. Virulence and cooperative social behaviour of the bacterium Pseudomonas aeruginosa rely on the quorum-sensing (QS) controlled production of extracellular products (public goods). Hence QS is an attractive target for anti-virulence interventions. During colonization, non-cooperating (and hence less virulent) P. aeruginosa QS-mutants, benefiting from public goods provided by wild type isolates, naturally increase in frequency providing a relative protection from invasive infection. We hypothesized that inhibition of QS-mediated gene expression removes this growth advantage and selection of less virulent QS-mutants, and maintains the predominance of more virulent QS-wild type bacteria. We addressed this possibility in a placebo-controlled trial investigating the anti-QS properties of azithromycin, a macrolide antibiotic devoid of bactericidal activity on P. aeruginosa, but interfering with QS, in intubated patients colonized by P. aeruginosa. In the absence of azithromycin, non-cooperating (and hence less virulent) lasR (QS)-mutants increased in frequency over time. Azithromycin significantly reduced QS-gene expression measured directly in tracheal aspirates. Concomitantly the advantage of lasR-mutants was lost and virulent wild-type isolates predominated during azithromycin treatment. We confirmed these results in vitro with fitness and invasion experiments. Azithromycin reduced growth rate of the wild-type, but not of the lasR-mutant. Furthermore, the lasR-mutant efficiently invaded wild-type populations in the absence, but not in the presence of azithromycin. These in vivo and in vitro results demonstrate that anti-virulence interventions based on QS-blockade diminish natural selection towards reduced virulence and therefore may increase the prevalence of more virulent genotypes in the Hospital environment. More generally, the impact of intervention on the evolution of virulence of pathogenic bacteria should be assessed.

Project description:Multidrug membrane transporters (efflux pumps) are responsible for multidrug resistance (MDR) and the low efficacy of therapeutic drugs. Noble metal nanoparticles (NPs) possess a high surface-area-to-volume ratio and size-dependent plasmonic optical properties, enabling them to serve both as imaging probes to study sized-dependent MDR and as potential drug carriers to circumvent MDR and enhance therapeutic efficacy. To this end, in this study, we synthesized three different sizes of silver nanoparticles (Ag NPs), 2.4 ± 0.7, 13.0 ± 3.1, and 92.6 ± 4.4 nm, functionalized their surface with a monolayer of 11-amino-1-undecanethiol (AUT), and covalently conjugated them with antibiotics (ofloxacin, Oflx) to prepare antibiotic drug nanocarriers with conjugation ratios of 8.6 × 102, 9.4 × 103, and 6.5 × 105 Oflx molecules per NP, respectively. We purified and characterized the nanocarriers and developed cell culture medium in which the cells grew normally and the nanocarriers were stable (non-aggregated), to quantitatively study the size, dose, and efflux pump (MexAB-OprM) dependent inhibitory effect of the nanocarriers against two strains of Pseudomonas aeruginosa, WT (normal expression of MexAB-OprM) and ΔABM (deletion of MexAB-OprM). We found that the inhibitory effect of these nanocarriers highly depended on the sizes of NPs, the doses of antibiotic, and the expression of MexAB-OprM. The same amount of Oflx on the largest nanocarriers (92.6 ± 4.4 nm) showed the highest inhibitory effect (the lowest minimal inhibitory concentration) against P. aeruginosa. Surprisingly, the smallest nanocarriers (2.4 ± 0.7 nm) exhibited a lower inhibitory effect than free Oflx. The results suggest that size-dependent multivalent effects, the distribution and localization of Oflx (pharmacodynamics), and the efflux of Oflx all play a role in the inhibitory effects. Control experiments using three sizes of AgMUNH2 NPs (absence of Oflx) showed that these NPs do not exhibit any significant inhibitory activity toward both strains. These new findings demonstrate the need for and possibility of designing optimal sized antibiotic nanocarriers to achieve the highest efficacy against P. aeruginosa.

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Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa.

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Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa.

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