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Periplasmic Targets for the Development of Effective Antimicrobials against Gram-Negative Bacteria.

ABSTRACT: Antibiotic resistance has emerged as a serious threat to global public health in recent years. Lack of novel antimicrobials, especially new classes of compounds, further aggravates the situation. For Gram-negative bacteria, their double layered cell envelope and an array of efflux pumps act as formidable barriers for antimicrobials to penetrate. While cytoplasmic targets are hard to reach, proteins in the periplasm are clearly more accessible, as the drug only needs to breach the outer membrane. In this review, we summarized recent efforts on the validation and testing of periplasmic proteins as potential antimicrobial targets and the development of related inhibitors that either inhibit the growth of a bacterial pathogen or reduce its virulence during interaction with host cells. We conclude that the periplasm contains a promising pool of novel antimicrobial targets that should be scrutinized more closely for the development of effective treatment against multidrug-resistant Gram-negative bacteria.

SUBMITTER: Pandeya A

PROVIDER: S-EPMC8187054 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Antibiotics are a medical wonder, but an increasing frequency of resistance among most human pathogens is rendering them ineffective. If this trend continues, the consequences for public health and for the general community could be catastrophic. The current clinical pipeline, however, is very limited and is dominated by derivatives of established classes, the "me too" compounds. Here, we have exploited our recent identification of a bacterial toxin to transform it into antibiotics active on multidrug-resistant (MDR) gram-positive and -negative bacterial pathogens. We generated a new family of peptidomimetics-cyclic heptapseudopeptides-inspired from a natural bacterial peptide. Out of the 4 peptides studied, 2 are effective against methicillin-resistant Staphylococcus aureus (MRSA) in mild and severe sepsis mouse models without exhibiting toxicity on human erythrocytes and kidney cells, zebrafish embryos, and mice. These new compounds are safe at their active doses and above, without nephrotoxicity. Efficacy was also demonstrated against Pseudomonas aeruginosa and MRSA in a mouse skin infection model. Importantly, these compounds did not result in resistance after serial passages for 2 weeks and 4 or 6 days' exposure in mice. Activity of heptapseudopeptides was explained by the ability of unnatural amino acids to strengthen dynamic association with bacterial lipid bilayers and to induce membrane permeability, leading to bacterial death. Based on structure determination, we showed that cationic domains surrounded by an extended hydrophobic core could improve bactericidal activity. Because 2 peptide analogs, Pep 16 and Pep19, are effective against both MRSA and P. aeruginosa in severe sepsis and skin infection models, respectively, we believe that these peptidomimetics are promising lead candidates for drug development. We have identified potential therapeutic agents that can provide alternative treatments against antimicrobial resistance. Because the compounds are potential leads for therapeutic development, the next step is to start phase I clinical trials.

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Periplasmic Targets for the Development of Effective Antimicrobials against Gram-Negative Bacteria.

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