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Peptides derived from non-immune proteins showed potent in vitro antimicrobial activity.Nearly 90% of peptides tested exhibited immunomodulatory effects.Lead peptides displayed anti-infective efficacy in preclinical mouse models, effectively reducing infections. Encrypted peptides (EPs) have been recently described as a new class of antimicrobial molecules. They have been found in numerous organisms and have been proposed to have a role in host immunity and as alternatives to conventional antibiotics. Intriguingly, many of these EPs are found embedded in proteins unrelated to the immune system, suggesting that immunological responses extend beyond traditional host immunity proteins. To test this idea, we synthesized and analyzed representative peptides derived from non-immune human proteins for their ability to exert antimicrobial and immunomodulatory properties. Most of the tested peptides from non-immune proteins, derived from structural proteins as well as proteins from the nervous and visual systems, displayed potent in vitro antimicrobial activity. These molecules killed bacterial pathogens by targeting their membrane, and those originating from the same region of the body exhibited synergistic effects when combined. Beyond their antimicrobial properties, nearly 90% of the peptides tested exhibited immunomodulatory effects, modulating inflammatory mediators, such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein-1 (MCP-1). Moreover, eight of the peptides identified, collagenin-3 and 4, zipperin-1 and 2, and immunosin-2, 3, 12, and 13, displayed anti-infective efficacy in two different preclinical mouse models, reducing bacterial infections by up to four orders of magnitude. Altogether, our results support the hypothesis that peptides from non-immune proteins may have a role in host immunity. These results potentially expand our notion of the immune system to include previously unrecognized proteins and peptides that may be activated upon infection to confer protection to the host. [Display omitted] The exploration of encrypted peptides and their antimicrobial properties has progressed over nearly a decade, now achieving Technology Readiness Levels 3/4 in laboratory settings. While these advances are promising, significant challenges must be addressed before full-scale implementation is feasible. The primary challenge lies in experimentally validating the in vivo expression and cleavage of parent proteins into encrypted peptides, either individually or in combination, at levels sufficient to exhibit antimicrobial activity. Key areas for further investigation include: (i) Overexpression studies: non-immune-related parent proteins should be overexpressed to determine whether the encrypted peptides exhibit the expected antimicrobial activity when produced at physiological levels. (ii) Knockout models: developing knockout models lacking the parent proteins of encrypted peptides could provide direct evidence of their functional roles by observing whether bacterial proliferation increases in their absence. (iii) In vivo experiments: using knockout mouse strains in in vivo experiments could reveal whether these animals show increased susceptibility to pathogenic infections, thereby validating the protective role of these peptides. Additionally, these peptides can be further explored and chemically modified to create more stable derivatives for direct application in clinical infection scenarios. However, transitioning from laboratory research to practical applications will require addressing key challenges, including optimizing peptide stability, bioavailability, and safety. Encrypted peptides derived from non-immune proteins exhibit potent antimicrobial and immunomodulatory properties. These peptides effectively kill bacterial pathogens, modulate immune mediators, and show anti-infective efficacy in preclinical models. The findings suggest that host immunity extends beyond traditional immune proteins, potentially broadening our current understanding of the immune system.

Klebsiella pneumoniae is becoming increasingly difficult to treat as multidrug-resistant (MDR) strains become more prevalent. The formation of biofilm heightens this threat by embedding bacterial cells in a polysaccharide-rich matrix that limits antibiotic penetration. Here we dissect the anti-biofilm bovine host-defense cathelicidin peptide fragment bac7 (1-35), exploring its anti-biofilm mechanism, evaluating its ability to curb colonization of the vital organs by hypervirulent K. pneumoniae, and testing its breadth of activity against diverse clinical isolates. Transcriptomic profiling revealed that bac7 (1-35) simultaneously compromises the bacterial membrane and inhibits ribosomal function, a dual assault that precipitates rapid biofilm collapse and blocks bacterial spread. Further, bac7 (1-35) eradicated the strongest biofilms produced by MDR clinical isolates in the Multidrug-Resistant Organism Repository and Surveillance Network (MRSN) diversity panel. Although bac7 (1-35) kills bacterial cells via a cytosolic mechanism, membrane interaction profiles varied among MRSN isolates, correlating with differential peptide translocation. In a delayed-treatment murine skin-abscess model, bac7 (1-35) halted in vivo colonization of the vital organs by the hypervirulent strain NTUH-K2044. Collectively, these results delineate a multifaceted mode of action for bac7 (1-35) and underscore its therapeutic promise against biofilm-associated MDR K. pneumoniae infections.

Peptides from frogs are promising antibiotic candidates.Frog-derived synthetic peptides selectively targeted Gram-negative pathogens, sparing beneficial microbiota and human cells.Structure-guided modifications improved the antimicrobial potency by optimizing hydrophobicity and net charge.Lead peptides effectively reduced bacterial loads in murine models of Pseudomonas aeruginosa and Acinetobacter baumannii infections without toxicity. Novel antibiotics are urgently needed since bacteria are becoming increasingly resistant to existing antimicrobial drugs. Furthermore, available antibiotics are broad spectrum, often causing off-target effects on host cells and the beneficial microbiome. To overcome these limitations, we used structure-guided design to generate synthetic peptides derived from Andersonin-D1, an antimicrobial peptide (AMP) produced by the odorous frog Odorrana andersonii. We found that both hydrophobicity and net charge were critical for its bioactivity, enabling the design of novel, optimized synthetic peptides. These peptides selectively targeted Gram-negative pathogens in single cultures and complex microbial consortia, showed no off-target effects on human cells or beneficial gut microbes, and did not select for bacterial resistance. Notably, they also exhibited in vivo activity in two preclinical murine models. Overall, we present synthetic peptides that selectively target pathogenic infections and offer promising preclinical antibiotic candidates. [Display omitted] Synthetic peptides, inspired by the natural defenses of amphibians, demonstrate selective activity against Gram-negative pathogens while sparing the gut microbiota and Gram-positive strains. Rationally designed peptides showed remarkable potency, exhibiting no signs of resistance or toxicity. These results underscore the potential of peptide-based antibiotics to tackle multidrug-resistant bacterial infections. Peptides represent highly promising scaffolds for drug development, offering tunable properties and versatility regarding their targets. Synthetic peptides are at the forefront of innovation in combating antibiotic resistance due to their modular nature, which enables precise design optimization. Currently in the preclinical phase [Technology Readiness Level (TRL) 3 or 4], these peptide molecules have shown robust efficacy in both in vitro and animal models, underscoring their potential as next-generation therapeutics. Recent advancements in rational peptide design, enhanced by machine learning and structure-guided approaches, are significantly improving antimicrobial peptide (AMP) potency, stability, and selectivity. Narrow-spectrum AMPs, designed to target specific pathogens, not only reduce the risk of antimicrobial resistance, but also help preserve the microbiome. Furthermore, consortia-based experiments evaluating peptides in complex bacterial communities are refining their application against multidrug-resistant infections. With continuous investment and technological innovation, AMPs are on track to enter clinical trials within the next decade. Addressing scalability and regulatory challenges will be critical to unlocking their full potential as precision-based therapies, ultimately providing an adaptable and effective solution for tackling resistant infections.

The 40 amino acid residues peptide MciZ ( M other C ell I nhibitor of Fts Z ) represents a promising antibacterial agent as it is an effective inhibitor of bacterial cell division, Z-ring formation and localization. However, its efficacy is limited to Gram-positive bacteria as MciZ is unable to penetrate into Gram-negative organisms. In this study, we report the synthesis of plasmonic silver chloride nanoparticles stabilized by MciZ (NP/MciZ). NP/MciZ were synthesized using a fast and green route under blue light irradiation. Electron microscopy showed that NP/MciZ were enveloped by a peptide layer responsible for colloidal stability. X-ray diffraction analysis showed that silver chloride nanoparticles were crystalline in nature with small proportion of metallic silver. NP/MciZ showed a dose-dependent cytotoxicity against mammalian VERO cells. However, NP/MciZ exhibited remarkable antibacterial activity against Gram-positive bacterium B. megaterium comparable to MciZ. Furthermore, NP/MciZ showed similar antimicrobial activity against the Gram-negative bacterium E. coli and the yeast C. albicans . The photochemically-generated NP/MciZ presented here is a new organic–inorganic hybrid nanomaterial and has potential for biomedical or other applications.

Molecular de-extinction aims at resurrecting molecules to solve antibiotic resistance and other present-day biological and biomedical problems. Here we show that deep learning can be used to mine the proteomes of all available extinct organisms for the discovery of antibiotic peptides. We trained ensembles of deep-learning models consisting of a peptide-sequence encoder coupled with neural networks for the prediction of antimicrobial activity and used it to mine 10,311,899 peptides. The models predicted 37,176 sequences with broad-spectrum antimicrobial activity, 11,035 of which were not found in extant organisms. We synthesized 69 peptides and experimentally confirmed their activity against bacterial pathogens. Most peptides killed bacteria by depolarizing their cytoplasmic membrane, contrary to known antimicrobial peptides, which tend to target the outer membrane. Notably, lead compounds (including mammuthusin-2 from the woolly mammoth, elephasin-2 from the straight-tusked elephant, hydrodamin-1 from the ancient sea cow, mylodonin-2 from the giant sloth and megalocerin-1 from the extinct giant elk) showed anti-infective activity in mice with skin abscess or thigh infections. Molecular de-extinction aided by deep learning may accelerate the discovery of therapeutic molecules. Deep learning can be used to mine the proteomes of all available extinct organisms for the discovery of compounds with antibiotic properties.

COVID-19 has led to over 3.47 million deaths worldwide and continues to devastate primarily middle- and low-income countries. High-frequency testing has been proposed as a potential solution to prevent outbreaks. However, current tests are not sufficiently low-cost, rapid, or scalable to enable broad COVID-19 testing. Here, we describe LEAD (Low-cost Electrochemical Advanced Diagnostic), a diagnostic test that detects severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 6.5 min and costs $1.50 per unit to produce using easily accessible and commercially available materials. LEAD is highly sensitive toward SARS-CoV-2 spike protein (limit of detection = 229 fg·mL−1) and displays an excellent performance profile using clinical saliva (100.0% sensitivity, 100.0% specificity, and 100.0% accuracy) and nasopharyngeal/oropharyngeal (88.7% sensitivity, 86.0% specificity, and 87.4% accuracy) samples. No cross-reactivity was detected with other coronavirus or influenza strains. Importantly, LEAD also successfully diagnosed the highly contagious SARS-CoV-2 B.1.1.7 UK variant. The device presents high reproducibility under all conditions tested and preserves its original sensitivity for 5 d when stored at 4 °C in phosphate-buffered saline. Our low-cost and do-it-yourself technology opens new avenues to facilitate high-frequency testing and access to much-needed diagnostic tests in resource-limited settings and low-income communities.

The rise of antibiotic-resistant pathogens, particularly gram-negative bacteria, highlights the urgent need for novel therapeutics. Drug-resistant infections now contribute to approximately 5 million deaths annually, yet traditional antibiotic discovery has significantly stagnated. Venoms form an immense and largely untapped reservoir of bioactive molecules with antimicrobial potential. In this study, we mined global venomics datasets to identify new antimicrobial candidates. Using deep learning, we explored 16,123 venom proteins, generating 40,626,260 venom-encrypted peptides. From these, we identified 386 candidates that are structurally and functionally distinct from known antimicrobial peptides. They display high net charge and elevated hydrophobicity, characteristics conducive to bacterial-membrane disruption. Structural studies revealed that many of these peptides adopt flexible conformations that transition to α-helical conformations in membrane-mimicking environments, supporting their antimicrobial potential. Of the 58 peptides selected for experimental validation, 53 display potent antimicrobial activity. Mechanistic assays indicated that they primarily exert their effects through bacterial-membrane depolarization, mirroring AMP-like mechanisms. In a murine model of Acinetobacter baumannii infection, lead peptides significantly reduced bacterial burden without observable toxicity. Our findings demonstrate that venoms are a rich source of previously hidden antimicrobial scaffolds, and that integrating large-scale computational mining with experimental validation can accelerate the discovery of urgently needed antibiotics. Researchers used artificial intelligence to mine global venom proteomes and discovered novel peptides with antimicrobial activity. Several candidates showed efficacy against drug-resistant bacteria in laboratory and animal tests.

Peptides are potential therapeutic alternatives against global diseases, such as antimicrobial-resistant infections and cancer. Venoms are a rich source of bioactive peptides that have evolved over time to act on specific targets of the prey. Peptides are one of the main components responsible for the biological activity and toxicity of venoms. South American organisms such as scorpions, snakes, and spiders are important producers of a myriad of peptides with different biological activities. In this review, we report the main venom-derived peptide families produced from South American organisms and their corresponding activities and biological targets.

Plants are extensively used in traditional medicine, and several plant antimicrobial peptides have been described as potential alternatives to conventional antibiotics. However, after more than four decades of research no plant antimicrobial peptide is currently used for treating bacterial infections, due to their length, post-translational modifications or  high dose requirement for a therapeutic effect . Here we report the design of antimicrobial peptides derived from a guava glycine-rich peptide using a genetic algorithm. This approach yields guavanin peptides, arginine-rich α-helical peptides that possess an unusual hydrophobic counterpart mainly composed of tyrosine residues. Guavanin 2 is characterized as a prototype peptide in terms of structure and activity. Nuclear magnetic resonance analysis indicates that the peptide adopts an α-helical structure in hydrophobic environments. Guavanin 2 is bactericidal at low concentrations, causing membrane disruption and triggering hyperpolarization. This computational approach for the exploration of natural products could be used to design effective peptide antibiotics. Antimicrobial peptides are considered promising alternatives to antibiotics. Here the authors developed a computational algorithm that starts with peptides naturally occurring in plants and optimizes this starting material to yield new variants which are highly distinct from the parent peptide.