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Patterns of cross-resistance and collateral sensitivity between clinical antibiotics and natural antimicrobials.

ABSTRACT: Bacteria interact with a multitude of other organisms, many of which produce antimicrobials. Selection for resistance to these antimicrobials has the potential to result in resistance to clinical antibiotics when active compounds target the same bacterial pathways. The possibility of such cross-resistance between natural antimicrobials and antibiotics has to our knowledge received very little attention. The antimicrobial activity of extracts from seaweeds, known to be prolific producers of antimicrobials, is here tested against Staphylococcus aureus isolates with varied clinical antibiotic resistance profiles. An overall effect consistent with cross-resistance is demonstrated, with multidrug-resistant S. aureus strains being on average more resistant to seaweed extracts. This pattern could potentially indicate that evolution of resistance to antimicrobials in the natural environment could lead to resistance against clinical antibiotics. However, patterns of antimicrobial activity of individual seaweed extracts vary considerably and include collateral sensitivity, where increased resistance to a particular antibiotic is associated with decreased resistance to a particular seaweed extract. Our correlation-based methods allow the identification of antimicrobial extracts bearing most promise for downstream active compound identification and pharmacological testing.

SUBMITTER: Colclough A

PROVIDER: S-EPMC6503891 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Patterns of cross-resistance and collateral sensitivity between clinical antibiotics and natural antimicrobials.

Colclough Abigail A Corander Jukka J Sheppard Samuel K SK Bayliss Sion C SC Vos Michiel M

Evolutionary applications 20190128 5

Bacteria interact with a multitude of other organisms, many of which produce antimicrobials. Selection for resistance to these antimicrobials has the potential to result in resistance to clinical antibiotics when active compounds target the same bacterial pathways. The possibility of such cross-resistance between natural antimicrobials and antibiotics has to our knowledge received very little attention. The antimicrobial activity of extracts from seaweeds, known to be prolific producers of antim ...[more]

PMID: 31080502

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Project description:Mutations conferring resistance to one antibiotic can increase (cross-resistance) or decrease (collateral sensitivity) resistance to others. Antibiotic combinations displaying collateral sensitivity could be used in treatments that slow resistance evolution. However, lab-to-clinic translation requires understanding whether collateral effects are robust across different environmental conditions. Here, we isolated and characterized resistant mutants of Escherichia coli using five antibiotics, before measuring collateral effects on resistance to other paired antibiotics. During both isolation and phenotyping, we varied conditions in ways relevant in nature (pH, temperature, and bile). This revealed that local abiotic conditions modified expression of resistance against both the antibiotic used during isolation and other antibiotics. Consequently, local conditions influenced collateral sensitivity in two ways: by favoring different sets of mutants (with different collateral sensitivities) and by modifying expression of collateral effects for individual mutants. These results place collateral sensitivity in the context of environmental variation, with important implications for translation to real-world applications. IMPORTANCE When bacteria become resistant to an antibiotic, the genetic changes involved sometimes increase (cross-resistance) or decrease (collateral sensitivity) their resistance to other antibiotics. Antibiotic combinations showing repeatable collateral sensitivity could be used in treatment to slow resistance evolution. However, collateral sensitivity interactions may depend on the local environmental conditions that bacteria experience, potentially reducing repeatability and clinical application. Here, we show that variation in local conditions (pH, temperature, and bile salts) can influence collateral sensitivity in two ways: by favoring different sets of mutants during bacterial resistance evolution (with different collateral sensitivities to other antibiotics) and by modifying expression of collateral effects for individual mutants. This suggests that translation from the lab to the clinic of new approaches exploiting collateral sensitivity will be influenced by local abiotic conditions.

Project description:The alarming rise in antibiotic resistance has led to an increase in patient mortality and health care costs. This problem is compounded by the absence of new antibiotics close to regulatory approval. Acinetobacter baumannii is a human pathogen that causes infections primarily in patients in intensive care units (ICUs) and is highly antibiotic resistant. Colistin is one of the last-line antibiotics for treating A. baumannii infections; however, colistin-resistant strains are becoming increasingly common. This cationic antibiotic attacks negatively charged bacterial membranes in a manner similar to that seen with cationic antimicrobials of the innate immune system. We therefore set out to determine if the increasing use of colistin, and emergence of colistin-resistant strains, is concomitant with the generation of cross-resistance to host cationic antimicrobials. We found that there is indeed a positive correlation between resistance to colistin and resistance to the host antimicrobials LL-37 and lysozyme among clinical isolates. Importantly, isolates obtained before and after treatment of individual patients demonstrated that colistin use correlated with increased resistance to cationic host antimicrobials. These data reveal the overlooked risk of inducing cross-resistance to host antimicrobials when treating patients with colistin as a last-line antibiotic. IMPORTANCE Increased use of the cationic antibiotic colistin to treat multidrug-resistant Acinetobacter baumannii has led to the development of colistin-resistant strains. Here we report that treatment of patients with colistin can induce not only increased resistance to colistin but also resistance to host cationic antimicrobials. This worrisome finding likely represents an example of a broader trend observed in other bacteria against which colistin is used therapeutically such as Pseudomonas aeruginosa and Klebsiella pneumoniae. Furthermore, these data suggest that the possible future use of an array of cationic antimicrobial peptides in development as therapeutics may have unintended negative consequences, eventually leading to the generation of hypervirulent strains that are resistant to innate host defenses. The potential for the induction of cross-resistance to innate immune antimicrobials should be considered during the development of new therapeutics.

Dataset Information

Patterns of cross-resistance and collateral sensitivity between clinical antibiotics and natural antimicrobials.

Publications

Patterns of cross-resistance and collateral sensitivity between clinical antibiotics and natural antimicrobials.

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