Evolutionary constraints on the acquisition of antimicrobial peptide resistance in bacterial pathogens

Jangir, Pramod Kumar; Ogunlana, Lois; MacLean, R. Craig

doi:10.1016/j.tim.2021.03.007

Cited by 26 publications

(25 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Antimicrobial peptides (AMPs) are multifunctional molecules found among all kingdoms of life that act as key components of the innate immune system of metazoans by modulating immune responses and defending against invading pathogens 1,2 . AMPs are potent antimicrobials with desirable pharmacodynamic properties and a low rate of resistance evolution [3][4][5][6] . Given these benefits, there is widespread interest in the development of natural and synthetic AMPs for therapeutic use [7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

The evolution of colistin resistance increases bacterial resistance to host antimicrobial peptides and virulence

Jangir

Ogunlana

Szili

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Antimicrobial peptides (AMPs) offer a promising solution to the antibiotic resistance crisis. However, an unresolved serious concern is that the evolution of resistance to therapeutic AMPs may generate cross-resistance to host AMPs, compromising a cornerstone of the innate immune response. We systematically tested this hypothesis using globally disseminated mobile colistin resistance (MCR) that has been selected by the use of colistin in agriculture and medicine. Here we show that MCR provides a selective advantage to E. coli in the presence of key AMPs from humans and agricultural animals by increasing AMP resistance. Moreover, MCR promotes bacterial growth in human serum and increases virulence in a Galleria mellonella infection model. Our study shows how the anthropogenic use of AMPs can drive the accidental evolution of resistance to the innate immune system of humans and animals. These findings have major implications for the design and use of therapeutic AMPs and they suggest that MCR will be difficult to eradicate, even if colistin use is withdrawn.

show abstract

Section: Introductionmentioning

confidence: 99%

The evolution of colistin resistance increases bacterial resistance to host antimicrobial peptides and virulence

Jangir

Ogunlana

Szili

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“… 1 Because of this and because, unlike clinically relevant antibiotics, HDPs and AMPs are produced by metazoans to counter infections, there is also interest in understanding how they have remained effective throughout evolutionary history. 2 …”

mentioning

confidence: 99%

Temporin B Forms Hetero-Oligomers with Temporin L, Modifies Its Membrane Activity, and Increases the Cooperativity of Its Antibacterial Pharmacodynamic Profile

et al. 2022

View full text Add to dashboard Cite

The pharmacodynamic profile of antimicrobial peptides (AMPs) and their in vivo synergy are two factors that are thought to restrict resistance evolution and ensure their conservation. The frog Rana temporaria secretes a family of closely related AMPs, temporins A–L, as an effective chemical dermal defense. The antibacterial potency of temporin L has been shown to increase synergistically in combination with both temporins B and A, but this is modest. Here we show that the less potent temporin B enhances the cooperativity of the in vitro antibacterial activity of the more potent temporin L against EMRSA-15 and that this may be associated with an altered interaction with the bacterial plasma membrane, a feature critical for the antibacterial activity of most AMPs. Addition of buforin II, a histone H2A fragment, can further increase the cooperativity. Molecular dynamics simulations indicate temporins B and L readily form hetero-oligomers in models of Gram-positive bacterial plasma membranes. Patch-clamp studies show transmembrane ion conductance is triggered with lower amounts of both peptides and more quickly when used in combination, but conductance is of a lower amplitude and pores are smaller. Temporin B may therefore act by forming temporin L/B hetero-oligomers that are more effective than temporin L homo-oligomers at bacterial killing and/or by reducing the probability of the latter forming until a threshold concentration is reached. Exploration of the mechanism of synergy between AMPs isolated from the same organism may therefore yield antibiotic combinations with advantageous pharmacodynamic properties.

show abstract

“…Antimicrobial peptides (AMPs) are components of the innate immune systems of many animals and plants and have been proposed as good candidates for treating multidrug resistant infections where other antibiotics have failed (Deslouches et al 2015; Mahlapuu et al 2016; Lei et al 2019). AMPs derived from natural defensive peptides have advantages compared to traditional antibiotics thanks to their broad-spectrum activity, ability to treat biofilm-embedded populations and observed evolutionary constraints that limit the rapid acquisition of AMP resistance (Lei et al 2019; Deslouches et al 2020; Jangir et al 2021). In fact, numerous AMPs, including daptomycin, vancomycin and bacitracin, have been approved by the FDA, and several other AMPs, including WLBU2, are under clinical trials (Greber and Dawgul 2017).…”

Section: Discussionmentioning

confidence: 99%

“…During antibiotic development, we must anticipate possible mechanisms of resistance in their design (Brockhurst et al 2019; MacLean 2020). Furthermore, to broaden use of AMPs in clinical settings we must explore evolutionary, genetic, and phenotypic barriers to AMP resistance in relevant pathogens (Jangir et al 2021). We often read claims of new ‘evolution-proof’ antibiotics (Zasloff 2002; Ling et al 2015), but here we further demonstrate that the absence of resistance mechanisms can result from insufficient sampling of genetic diversity (Bell and MacLean 2018).…”

Section: Discussionmentioning

confidence: 99%

Experimental evolution to identify undescribed mechanisms of resistance to a novel cationic peptide antibiotic

Santos-López

Fritz

Lombardo

et al. 2020

Preprint

View full text Add to dashboard Cite

A key strategy for resolving the antibiotic resistance crisis is the development of new drugs with antimicrobial properties. The engineered cationic antimicrobial peptide WLBU2 (also known as PLG0206) is a promising broad-spectrum antimicrobial compound that has completed Phase I clinical studies. It has activity against Gram-negative and Gram-positive bacteria including infections associated with biofilm. No definitive mechanisms of resistance to WLBU2 have been identified. Here, we used experimental evolution under different levels of mutation supply and whole genome sequencing (WGS) to detect the genetic pathways and probable mechanisms of resistance to this peptide. We propagated populations of wild-type and mutator Pseudomonas aeruginosa in the presence of WLBU2 and performed WGS of evolved populations and clones. Populations that survived WLBU2 treatment acquired a minimum of two mutations, making the acquisition of resistance more difficult than for most antibiotics, which can be tolerated by mutation of a single target. Major targets of resistance to WLBU2 included the orfN and pmrB genes, previously described to confer resistance to other cationic peptides. More surprisingly, mutations that increase aggregation such as the wsp pathway were also selected despite the ability of WLBU2 to kill cells growing in a biofilm. The results show how the experimental evolution and WGS can identify genetic targets and actions of new antimicrobial compounds and predict pathways to resistance of new antibiotics in clinical practice.

show abstract

Evolutionary constraints on the acquisition of antimicrobial peptide resistance in bacterial pathogens

Cited by 26 publications

References 15 publications

The evolution of colistin resistance increases bacterial resistance to host antimicrobial peptides and virulence

The evolution of colistin resistance increases bacterial resistance to host antimicrobial peptides and virulence

Temporin B Forms Hetero-Oligomers with Temporin L, Modifies Its Membrane Activity, and Increases the Cooperativity of Its Antibacterial Pharmacodynamic Profile

Experimental evolution to identify undescribed mechanisms of resistance to a novel cationic peptide antibiotic

Contact Info

Product

Resources

About