Chemical-genetic profiling reveals limited cross-resistance between antimicrobial peptides with different modes of action

Kintses, Bálint; Jangir, Pramod Kumar; Fekete, G.; Számel, Mónika; Méhi, Orsolya; Spohn, Réka; Daruka, Lejla; Martins, Ana; Hosseinnia, Ali; Gagarinova, Alla; Kim, Sun‐Young; Phanse, Sadhna; Csörgő, Bálint; Györkei, Ádám; Ari, Eszter; Lázár, Viktória; Nagy, István; Babu, Mohan; Pál, Csaba; Papp, Balázs

doi:10.1038/s41467-019-13618-z

Cited by 34 publications

(44 citation statements)

References 70 publications

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“…have shown that ARB frequently present collateral sensitivity to antimicrobial peptides (Lázár et al, 2018) and that, importantly, some antimicrobial peptides present limited resistance or crossresistance (Kintses et al, 2019;Spohn et al, 2019). From a conservative point of view, based on the use of the drugs we already have, it would be desirable to fight AR using evolution-based strategies for developing new drugs or treatment strategies.…”

Section: Controlling Resistance: Local and Global Interventionsmentioning

confidence: 99%

“…Furthermore, antimicrobial peptides, with a dual role as immunomodulators and antimicrobials, may also help fight infections ( Hancock et al, 2016 ). In fact, some works have shown that ARB frequently present collateral sensitivity to antimicrobial peptides ( Lázár et al, 2018 ) and that, importantly, some antimicrobial peptides present limited resistance or cross-resistance ( Kintses et al, 2019 ; Spohn et al, 2019 ).…”

Section: Controlling Resistance: Local and Global Interventionsmentioning

confidence: 99%

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Antibiotic Resistance: Moving From Individual Health Norms to Social Norms in One Health and Global Health

et al. 2020

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Antibiotic resistance is a problem for human health, and consequently, its study had been traditionally focused toward its impact for the success of treating human infections in individual patients (individual health). Nevertheless, antibiotic-resistant bacteria and antibiotic resistance genes are not confined only to the infected patients. It is now generally accepted that the problem goes beyond humans, hospitals, or long-term facility settings and that it should be considered simultaneously in human-connected animals, farms, food, water, and natural ecosystems. In this regard, the health of humans, animals, and local antibiotic-resistance-polluted environments should influence the health of the whole interconnected local ecosystem (One Health). In addition, antibiotic resistance is also a global problem; any resistant microorganism (and its antibiotic resistance genes) could be distributed worldwide. Consequently, antibiotic resistance is a pandemic that requires Global Health solutions. Social norms, imposing individual and group behavior that favor global human health and in accordance with the increasingly collective awareness of the lack of human alienation from nature, will positively influence these solutions. In this regard, the problem of antibiotic resistance should be understood within the framework of socioeconomic and ecological efforts to ensure the sustainability of human development and the associated human-natural ecosystem interactions.

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Section: Controlling Resistance: Local and Global Interventionsmentioning

confidence: 99%

Section: Controlling Resistance: Local and Global Interventionsmentioning

confidence: 99%

Antibiotic Resistance: Moving From Individual Health Norms to Social Norms in One Health and Global Health

et al. 2020

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“…4a). Increase in PLL-FITC binding has previously also been correlated with increased susceptibility to the action of antimicrobial peptides (5, 32, 33). In contrast, zeta potential values did not show a strong correlation with Ped-488 (r 2 = 0.06, r s = −0.62, Fig.…”

Section: Resultsmentioning

confidence: 93%

Charged Gram-positive species sequester and decrease the potency of pediocin PA-1 in mixed microbial settings

Trivedi

Nair

2020

Preprint

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15Antimicrobial peptides (AMPs) have gained attention recently due to increasing antibiotic 16 resistance amongst pathogens. Most AMPs are cationic in nature and their preliminary 17 interactions with the negatively charged cell surface is mediated by electrostatic attraction. This 18 is followed by pore formation, which is either receptor-dependent or -independent and leads to 19 cell death. Typically, AMPs are characterized by their killing activity using bioactivity assays 20 to determine host range and degree of killing. However, cell surface binding is independent 21 from killing. Most of the studies performed to-date have attempted to quantify the peptide 22 binding using artificial membranes. Here, we use the narrow-spectrum class IIa bacteriocin 23 AMP pediocin PA-1 conjugated to a fluorescent dye as a probe to monitor cell surface binding. 24We developed a flow cytometry-based assay to quantify the strength of binding in target and 25 non-target species. Through our binding assays, we found a strong positive correlation between 26 cell surface charge and pediocin PA-1 binding. Interestingly, we also found inverse correlation 27 between zeta potential and pediocin PA-1 binding, the correlation coefficient for which 28 improved when only Gram-positives were considered. We also show the effect of the presence 29 of protein, salt, polycationic species, and other non-target species on the binding of pediocin 30PA-1 to the target organism. We conclude that the of presence of highly charged non-target 31 species, as well as solutes, can decrease the binding, and the apparent potency, of pediocin PA-32 1. Thus, these outcomes are highly significant to the use of pediocin PA-1 and related AMPs 33 in mixed microbial settings such as those found in the gut microbiota. 34 35

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“…Spohn et al (196) have highlighted the influence of physicochemical characteristics of HDPs, including the proportion of polar AAs, cationicity, and hydrophobicity, on the risk of developing HDP-related AMR, thereby providing invaluable insights into the design of future HDPs. Reassuringly, cross resistance between HDPs was found to be limited to those with similar modes of action, underscoring the importance and necessity of having HDPs with different antimicrobial mechanisms within the therapeutic armamentarium of antimicrobials (197). With the advancement in peptide design strategy, synthesis techniques and AI technology, it is hopeful that clinical deployment of HDP-based treatment for a range of diseases will soon become a reality.…”

Section: Risk Of Amr Related To Hdpmentioning

confidence: 99%

Strategies in Translating the Therapeutic Potentials of Host Defense Peptides

et al. 2020

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The golden era of antibiotics, heralded by the discovery of penicillin, has long been challenged by the emergence of antimicrobial resistance (AMR). Host defense peptides (HDPs), previously known as antimicrobial peptides, are emerging as a group of promising antimicrobial candidates for combatting AMR due to their rapid and unique antimicrobial action. Decades of research have advanced our understanding of the relationship between the physicochemical properties of HDPs and their underlying antimicrobial and non-antimicrobial functions, including immunomodulatory, anti-biofilm, and wound healing properties. However, the mission of translating novel HDP-derived molecules from bench to bedside has yet to be fully accomplished, primarily attributed to their intricate structure-activity relationship, toxicity, instability in host and microbial environment, lack of correlation between in vitro and in vivo efficacies, and dwindling interest from large pharmaceutical companies. Based on our previous experience and the expanding knowledge gleaned from the literature, this review aims to summarize the novel strategies that have been employed to enhance the antimicrobial efficacy, proteolytic stability, and cell selectivity, which are all crucial factors for bench-to-bedside translation of HDP-based treatment. Strategies such as residues substitution with natural and/or unnatural amino acids, hybridization, L-to-D heterochiral isomerization, C-and N-terminal modification, cyclization, incorporation with nanoparticles, and "smart design" using artificial intelligence technology, will be discussed. We also provide an overview of HDP-based treatment that are currently in the development pipeline.

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Chemical-genetic profiling reveals limited cross-resistance between antimicrobial peptides with different modes of action

Cited by 34 publications

References 70 publications

Antibiotic Resistance: Moving From Individual Health Norms to Social Norms in One Health and Global Health

Antibiotic Resistance: Moving From Individual Health Norms to Social Norms in One Health and Global Health

Charged Gram-positive species sequester and decrease the potency of pediocin PA-1 in mixed microbial settings

Strategies in Translating the Therapeutic Potentials of Host Defense Peptides

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