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Prolonged antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defense peptides
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2016 (English)In: Nature Communications, ISSN 2041-1723Article in journal (Other academic) Submitted
Abstract [en]

To combat the rapid increase in multi-drug resistant bacterial pathogens, the

clinical development of antimicrobial peptides (AMPs) with broad-spectrum

bactericidal activity is currently under evaluation. However, many of these

closely resemble products of the host innate immune system, and the

ramifications of prolonged bacterial exposure to host-derived AMPs are not

fully understood. Here we show that in vitro serial passage of a clinical

USA300 methicillin-resistant Staphylococcus aureus strain in a hostmimicking

environment containing host-derived AMPs results in the selection

of stable AMP-resistance. This phenotype coincided with diminished

susceptibility to clinically prescribed antibiotics and occurred in the absence

of a fitness cost to the bacterium. Further, AMP-resistant S. aureus were

capable of causing invasive disease in mice and were less susceptible to

human defensins. These findings suggest that therapeutic use of AMPs could

select for virulent mutants with cross-resistance to both human defensins and

antibiotics, ultimately rendering us more susceptible to infection. Thus,

therapeutic use of AMPs and the implications of cross-resistance need to be

carefully monitored and evaluated.

Place, publisher, year, edition, pages
Keyword [en]
antimicrobial peptides, host defense peptides, antibiotic resistance
National Category
Pharmacology and Toxicology
URN: urn:nbn:se:uu:diva-281683OAI: oai:DiVA.org:uu-281683DiVA: diva2:918873
Available from: 2016-04-12 Created: 2016-03-29 Last updated: 2016-06-15
In thesis
1. Mechanisms and Biological Costs of Bacterial Resistance to Antimicrobial Peptides
Open this publication in new window or tab >>Mechanisms and Biological Costs of Bacterial Resistance to Antimicrobial Peptides
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The global increasing problem of antibiotic resistance necessarily drives the pursuit and discovery of new antimicrobial agents. Antimicrobial peptides (AMPs) initially seemed like promising new drug candidates. Already members of the innate immune system, it was assumed that they would be bioactive and non-toxic. Their common trait for fundamental, non-specific mode of action also seemed likely to reduce resistance development.

In this thesis, we demonstrate the ease with which two species of pathogenic bacteria, the gram-negative Salmonella typhimurium (S. typhimurium), and the gram-positive Staphylococcus aureus (S. aureus), can gain increased tolerance and stable resistance to various AMPs. By serially passaging each bacterial species separately under increasing AMP selection pressure we observed increasing AMP tolerance. Resulting in independent bacterial lineages exposed to four different AMPs (including a two-AMP combination) that exhibited 2 to 16-fold increases in MIC. Substantial cross-resistance between the AMPs was observed. Additionally, the S. aureus mutants were found to be cross-resistant to human beta-defensins 1, 2, 3, and 4.

The LPS molecule, with mutations in the waaY, pmrB and phoP genes, was the principal target for S. typhimurium resistance development. The main target for S. aureus remained elusive. Reduced membrane potential was a common change for two of the mutants, but not for the others. All sequenced mutants had one or more mutations in various stress response pathways.

Fitness of the resistant mutants was assayed by growth rate analysis and in vitro virulence factor testing (e.g. survival response to bile, superoxide, acidic pH). Furthermore an in vivo survival/virulence test involving a mouse competition experiment (S. typhimurium) and sepsis model (S. aureus) was performed. In the absence of AMPs there was often little or no fitness reduction in the mutants. Our results suggest that AMP resistance mechanisms do not irrevocably weaken either species with regard to virulence characteristics or survival within the host.

In light of these findings, we suggest that the progression of therapeutic use of AMPs should proceed with great caution since otherwise we might select for AMP resistant mutants that are more resistant to our innate host defenses and thereby potentially more virulent.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 61 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1226
antimicrobial peptides, antibiotic resistance, fitness cost, Salmonella Typhimurium, Staphylococcus aureus, bile, serum, pH response, growth rate, mice, phoP, pmrB, waaY, LPS, LL-37, defensins, membrane potential
National Category
Microbiology in the medical area
Research subject
urn:nbn:se:uu:diva-284119 (URN)978-91-554-9579-4 (ISBN)
Public defence
2016-06-14, C8:305, BMC, Husargatan 3, Uppsala, 13:00 (English)
Available from: 2016-05-20 Created: 2016-04-15 Last updated: 2016-06-15

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Lofton, Hava
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