Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives

Garneau‐Tsodikova, Sylvie; Labby, Kristin Jansen

doi:10.1039/c5md00344j

Cited by 381 publications

(293 citation statements)

References 245 publications

(284 reference statements)

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“…Initially, nonproducer frequency increases fastest at intermediate antibiotic concentrations and increases slowest at high antibiotic concentrations. However, under the reasonable assumption that the antibiotic effect decreases over time [which could occur, for example, due to drug degradation (55) or bacterial adaptation (56)], the model predicts that the rate of change will accelerate in the latter case, as we indeed observed in our experiments.…”

Section: Theoretical Frameworksupporting

confidence: 67%

Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa

Vasse

Noble

Akhmetzhanov

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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.evolution | cooperation | antibiotics | social behavior | resistance P ublic goods production is a characteristic of a diverse range of taxa, from microbes to humans (1-3). Explaining the persistence of this costly behavior is challenging, because cheats can exploit the commons without contributing. Kin selection theory has proven to be a successful framework for addressing this question, with the central prediction that cooperation is favored by sufficient benefits to, and positive assortment between, cooperators (4-8). For example, recent study in experimental bacterial populations has elucidated mechanisms such as assortment emerging from limited or budding dispersal (9, 10) and kin discrimination (11, 12) that are consistent with kin selection fostering cooperative behaviors (e.g., refs. 8 and 13). However, despite this accumulating consensus, little is known about how social populations respond to differences and variation in abiotic and biotic components of their environment. In particular, it is unclear how ecological antagonisms affect the ability of cheats to invade cooperator communities.Cooperation can be affected by stress directly through differential selection on cooperative phenotypes (14, 15), or by inducing specific plastic behaviors (16-22), especially when cooperation leads to increased stress resistance. However, in the absence of a direct benefit of the cooperative behavior against stress, the ecological and evolutionary outcomes of the interactions between nondefensive public goods and stress responses are less clear and are potentially complex. Cooperation may be infl...

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Section: Theoretical Frameworksupporting

confidence: 67%

Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa

Vasse

Noble

Akhmetzhanov

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The aminoglycoside antibiotics (AGAs) are particularly attractive in this light as both their mechanism of antibacterial action and the common causes of resistance to them are well-understood. 6–9 Advantages of the AGAs as parents for optimization include their broad spectrum of activity, their non-allergenic character, and their lack of effect on the host intestinal microbiome. 9 In addition, AGAs have physicochemical properties consistent with suggested guidelines for the development of new antibacterial compounds, 10 and following decades of use in the clinic, their PK, PD and ADME properties are well-understood and largely predictable.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Design and Synthesis of Apramycin–Paromomycin Analogues: Importance of the Configuration at the 6′-Position and Differences between the 6′-Amino and Hydroxy Series

et al. 2017

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The preparation of a series of four analogues of the aminoglycoside antibiotics neomycin and paromomycin is described in which ring I, involved in critical binding interactions with the ribosomal target, is replaced by an apramycin-like dioxabicyclo[4.4.0]octane system. The effect of this modification is to lock the hydroxymethyl side chain of the neomycin or paromomycin ring I, as part of the dioxabicyclooctane ring, into either the gauche-gauche or the gauche-trans conformation (respectively axial or equatorial to the bicyclic system). The antiribosomal activity of these compounds is investigated with cell-free translation assays using both bacterial ribosomes and recombinant hybrid ribosomes carrying eukaryotic decoding A site cassettes. Compounds substituted with an equatorial hydroxyl or amino group in the newly formed ring are considerably more active than their axial diastereomers, lending strong support to crystallographically-derived models of aminoglycoside-ribosome interactions. One such bicyclic compound carrying an equatorial hydroxyl group has activity equal to that of the parent, yet displays better ribosomal selectivity, predictive of an enhanced therapeutic index. A paromomycin analog lacking the hydroxymethyl ring I side chain is considerably less active than the parent. Antibacterial activity against model Gram negative and Gram positive bacteria is reported, for selected compounds, as is activity against ESKAPE pathogens and recombinant bacteria carrying specific resistance determinants. Analogues with a bicyclic ring I carrying equatorial amino or hydroxyl groups mimicking the bound side chains of neomycin and paromomcyin, respectively, show excellent activity and, by virtue of their novel structure, retain this activity in strains that are insensitive to the parent compounds.

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“…Therefore, there is a need to develop simple and rapid methods of analysing aminoglycoside antibiotics in order to provide novel methods for TDM, which could essentially enable the more widespread use of these extremely effective antibiotics. Given their low resistance rates in comparison to other classes of antibiotics, 7, 9 the clinical importance of aminoglycosides is being reassessed and the use of novel assays and instrumentation is one way in which these antibiotics could be widely reintroduced into the healthcare system while maintaining patient safety.…”

Section: Introductionmentioning

confidence: 99%

High throughput LSPR and SERS analysis of aminoglycoside antibiotics

McKeating

Couture

Dinel

et al. 2016

Analyst

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Aminoglycoside antibiotics are used in the treatment of infections caused by Gram-negative bacteria, and are often dispensed only in severe cases due to their adverse side effects. Patients undergoing treatment with these antibiotics are therefore commonly subjected to therapeutic drug monitoring (TDM) to ensure a safe and effective personalised dosage. The ability to detect these antibiotics in a rapid and sensitive manner in human fluids is therefore of the utmost importance in order to provide effective monitoring of these drugs, which could potentially allow for a more widespread use of this class of antibiotics. Herein, we report on the detection of various aminoglycosides, by exploiting their ability to aggregate gold nanoparticles. The number and position of the amino groups of aminoglycoside antibiotics controlled the aggregation process. We investigated the complementary techniques of surface enhanced Raman spectroscopy (SERS) and localized surface plasmon resonance (LSPR) for dual detection of these aminoglycoside antibiotics and performed an in-depth study of the feasibility of carrying out TDM of tobramycin using a platform amenable to high throughput analysis. Herein, we also demonstrate dual detection of tobramycin using both LSPR and SERS in a single platform and within the clinically relevant concentration range needed for TDM of this particular aminoglycoside. Additionally we provide evidence that tobramycin can be detected in spiked human serum using only functionalised nanoparticles and SERS analysis.

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Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives

Cited by 381 publications

References 245 publications

Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa

Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa

Structure-Based Design and Synthesis of Apramycin–Paromomycin Analogues: Importance of the Configuration at the 6′-Position and Differences between the 6′-Amino and Hydroxy Series

High throughput LSPR and SERS analysis of aminoglycoside antibiotics

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