Structure-function-guided design of synthetic peptides with anti-infective activity derived from wasp venom

Boaro, Andreia; Ageitos, Lucía; Torres, Marcelo Der Torossian; Blasco, E.; Öztekin, Sebahat; Fuente-Núñez, César de la

doi:10.1016/j.xcrp.2023.101459

Cited by 13 publications

(12 citation statements)

References 79 publications

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“…The peptide antibiotic polymyxin B was used as a positive control in our studies 21 . In summary, SEPs did not permeabilize the outer membrane of bacteria to the level previously reported for AMPs 7,32 or EPs 21 , indicating that the mechanism of action of SEPs might be independent of outer membrane permeabilization.…”

Section: Introductionsupporting

confidence: 43%

“…Out of all 48 conditions tested, in 40 occasions SEPs tested depolarized the cytoplasmic membrane of bacteria more substantially than groups treated with polymyxin B, a control which displays certain level of depolarization 21 ( Figure S5a-i ). Overall, these data suggest that SEPs operate preferentially via depolarizing the cytoplasmic membrane as opposed to permeabilizing the outer membrane, revealing a mechanism that is distinct from that of conventional AMPs 7,32 and EPs 21 , which tend to target the outer membrane.…”

Section: Introductionmentioning

confidence: 82%

“…Current methods used to discover new molecules rely primarily on prospection of naturally occurring organisms, which is slow and upredictable as it relies on trial-and-error experimentation. Additional engineering of AMPs has leveraged heuristics whereby amino acid residues substitutions are introduced 7–11 , guided by alterations in physicochemical feature determinants known to contribute to membrane targeting and, ultimately, antimicrobial activity 4 . Recently, advances in machine learning 12,13 and methods 14 such as generic algorithms 15 and pattern recognition algorithms 16,17 have yielded improved peptides.…”

Section: Introductionmentioning

confidence: 99%

“…We drew on a list of 444,054 families of putative small proteins (referred to as the 444k set) that were previously predicted using a comparative genomic workflow. 7 Briefly, MetaProdigal 8 was used to annotate all open reading frames (ORFs), as short as 15 base pairs, on 128,368,337 contigs spanning more than 180 billion base pairs of sequenced DNA from 1,773 metagenomes from 263 healthy individuals sampled from four different major body sites. We filtered out ORFs that encode for proteins that are >50 amino acid residues in length and then clustered the remaining proteins based on sequence and length similarity using CD-Hit, 9 resulting in the 444k set.…”

Section: Introductionmentioning

confidence: 99%

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Human gut metagenomic mining reveals an untapped source of peptide antibiotics

Torres,

Brooks,

Cesaro

et al. 2023

Preprint

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Drug-resistant bacteria are outpacing traditional antibiotic discovery efforts. Here, we computationally mined 444,054 families of putative small proteins from 1,773 human gut metagenomes, identifying 323 peptide antibiotics encoded in small open reading frames (smORFs). To test our computational predictions, 78 peptides were synthesized and screened for antimicrobial activityin vitro, with 59% displaying activity against either pathogens or commensals. Since these peptides were unique compared to previously reported antimicrobial peptides, we termed themsmORF-encoded peptides (SEPs). SEPs killed bacteria by targeting their membrane, synergized with each other, and modulated gut commensals, indicating that they may play a role in reconfiguring microbiome communities in addition to counteracting pathogens. The lead candidates were anti-infective in both murine skin abscess and deep thigh infection models. Notably, prevotellin-2 fromPrevotella copripresented activity comparable to the commonly used antibiotic polymyxin B. We report the discovery of hundreds of peptide sequences in the human gut.

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Section: Introductionsupporting

confidence: 43%

Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human gut metagenomic mining reveals an untapped source of peptide antibiotics

Torres,

Brooks,

Cesaro

et al. 2023

Preprint

Self Cite

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“…To determine if 2 was permeabilizing the outer membrane, thus sensitizing P. aeruginosa to vancomycin, we performed permeabilization assays with the fluorescent probe N -phenylnaphthalen-1-amine (NPN) with vancomycin, 2 , and combinations of the two. NPN does not fluoresce significantly in water, but when the outer membrane is permeabilized, it can access the cytosolic membrane and fluoresce in the hydrophobic environment . This revealed that 2 does not permeabilize the outer membrane alone and that the combination of the two compounds does not differ from vancomycin alone (Figure B).…”

mentioning

confidence: 94%

Investigating the Role of Metabolism for Antibiotic Combination Therapies in Pseudomonas aeruginosa

Golden,

Post,

Rivera

et al. 2023

ACS Infect. Dis.

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Antibacterial resistance poses a severe threat to public health; an anticipated 14-fold increase in multidrug-resistant (MDR) bacterial infections is expected to occur by 2050. Contrary to antibiotics, combination therapies are the standard of care for antiviral and anticancer treatments, as synergistic drug–drug interactions can decrease dosage and resistance development. In this study, we investigated combination treatments of a novel succinate dehydrogenase inhibitor (promysalin) with specific inhibitors of metabolism and efflux alongside a panel of clinically approved antibiotics in synergy studies. Through these investigations, we determined that promysalin can work synergistically with vancomycin and antagonistically with aminoglycosides and a glyoxylate shunt pathway inhibitor at subinhibitory concentrations; however, these cooperative effects do not reduce minimum inhibitory concentrations. The variability of these results underscores the complexity of targeting metabolism for combination therapies in antibiotic development.

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