Biology subjects

Cesaro, A.

Publications and source records attributed to Cesaro, A..

3 recordsLinked to original sources

bioRxiv2024

Design of multimodal antibiotics against intracellular infections using deep learning

The rise of antimicrobial resistance has rendered many treatments ineffective, posing serious public health challenges. Intracellular infections are particularly difficult to treat since conventional antibiotics fail to neutralize pathogens hidden within human cells. However, designing molecules that penetrate human cells with preserved antimicrobial activity has historically been a major challenge. Here, we introduce ApexDuo, a multimodal artificial intelligence (AI) model for generating peptides with both cell- penetrating and antimicrobial properties. From a library of 50 million AI-generated compounds, we selected and characterized several candidates. Our lead, Turingcin-46, penetrated mammalian cells and reduced intracellular Staphylococcus aureus and Listeria monocytogenes. In mouse models of skin abscess and peritonitis, Turingcin-46 reduced bacterial loads by up to two orders of magnitude. In sum, ApexDuo generated multimodal peptide antibiotics, opening new avenues for designing molecules with more than one function.

synthetic biology↗

bioRxiv2024

Peptides from non-immune proteins target infections through antimicrobial and immunomodulatory properties

Encrypted peptides have been recently described as a new class of antimicrobial molecules. They have been proposed to play a role in host immunity and as alternatives to conventional antibiotics. Intriguingly, many of these peptides are found embedded in proteins unrelated to the immune system, suggesting that immunological responses may extend beyond traditional host immunity proteins. To test this idea, here we synthesized and tested representative peptides derived from non-immune proteins for their ability to exert antimicrobial and immunomodulatory properties. Our experiments revealed that 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 IL-6, TNF-, and 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 play 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.

microbiology↗

bioRxiv2023

Human gut metagenomic mining reveals an untapped source of peptide antibiotics

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 activity in vitro, with 59% displaying activity against either pathogens or commensals. Since these peptides were unique compared to previously reported antimicrobial peptides, we termed them smORF-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 from Prevotella copri presented activity comparable to the commonly used antibiotic polymyxin B. We report the discovery of hundreds of peptide sequences in the human gut.

bioengineering↗