dc.contributor.author
Antunes, Bernardo
dc.contributor.author
Zanchi, Caroline
dc.contributor.other
Johnston, Paul
dc.contributor.other
Maron, Bar
dc.contributor.other
Witzany, Christopher
dc.contributor.other
Regoes, Roland
dc.contributor.other
Hayouka, Zvi
dc.contributor.other
Rolff, Jens
dc.date.accessioned
2024-04-29T08:22:39Z
dc.date.available
2024-04-29T08:22:39Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/42566.2
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-42290.2
dc.description.abstract
The prevalence of antibiotic-resistant pathogens has become a major threat to public health, requiring swift initiatives for discovering new strategies to control bacterial infections. Hence, antibiotic stewardship and rapid diagnostics, but also the development, and prudent use, of novel effective antimicrobial agents are paramount. Ideally, these agents should be less likely to select for resistance in pathogens than currently available conventional antimicrobials. The usage of antimicrobial Peptides (AMPs), key components of the innate immune response, and combination therapies, have been proposed as strategies to diminish the emergence of resistance.
Herein, we investigated whether newly developed random antimicrobial peptide mixtures (RPMs) can significantly reduce the risk of resistance evolution in vitro to that of single sequence AMPs, using the ESKAPE pathogen Pseudomonas aeruginosa (P. aeruginosa) as a model Gram-negative bacterium. Infections of this pathogen are difficult to treat due the inherent resistance to many drug classes, enhanced by the capacity to form biofilms. P. aeruginosa was experimentally evolved in the presence of AMPs or RPMs, subsequentially assessing the extent of resistance evolution and cross-resistance/collateral sensitivity between treatments. Furthermore, the fitness costs of resistance on bacterial growth were studied, and whole-genome sequencing used to investigate which mutations could be candidates for causing resistant phenotypes. Lastly, changes in the pharmacodynamics of the evolved bacterial strains were examined.
Our findings suggest that using RPMs bears a much lower risk of resistance evolution compared to AMPs and mostly prevents cross-resistance development to other treatments, while maintaining (or even improving) drug sensitivity. This strengthens the case for using random cocktails of AMPs in favour of single AMPs, against which resistance evolved in vitro, further providing an alternative to classic antibiotics worth pursuing.
en
dc.publisher
PLOS Biology
dc.rights.uri
http://www.fu-berlin.de/sites/refubium/rechtliches/Nutzungsbedingungen
dc.subject
Random antimicrobial peptide mixtures (RPMs)
en
dc.subject
Pseudomonas aeruginosa
en
dc.subject
antibiotic resistance
en
dc.subject
whole-genome sequencing
en
dc.subject
pharmacodynamics experimental evolution
en
dc.subject.ddc
500 Natural sciences and mathematics::570 Life sciences::579 Microorganisms, fungi, algae
dc.title
The evolution of antimicrobial peptide resistance in Pseudomonas aeruginosa is severely constrained by random peptide mixtures
dc.contributor.type
data_collector
dc.contributor.type
data_manager
refubium.affiliation
Biologie, Chemie, Pharmazie
refubium.affiliation.other
Institut für Biologie / Arbeitsbereich Neurobiologie
refubium.funding.funder
fund_eu
refubium.isSupplementTo.doi
https://doi.org/10.1101/2024.02.22.581582
dcterms.accessRights.openaire
open access