Novel antibiotics effective against gram-positive and -negative multi-resistant bacteria with limited resistance

Abstract

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.

New Tricks for Old Guys: Recent Developments in the Chemistry, Biochemistry, Applications and Exploitation of Selected Species from the Lamiaceae Family

“…[56] O. vulgare is one of the main species of this genus and then the most studied, however, other minor species show interesting chemical composition associated with biological activities, for example a study of the chemical characterization and the evaluation of antimicrobial, enzyme inhibitory, and antioxidant activities of methanol and water extracts of Turkish O. onites has been recently reported. [424] In total 28 components belonging to polyphenols, flavonoids, terpenoids, organic acids and esters have been identified: 3-O-(4-coumaroyl)quinic acid (16), acacetin (17), cirsimaritin (14), naringenin (9), tuberonic acid glucoside (18), ferulic acid (3), apigenin-7,4'-dimethyl ether (19), azelaic acid (20), baicalin (21), casticin (22), cirsiliol (11), dihydrorobinetin (23), gardenin B (24), genkwanin (25), isoferulic acid (26), kaempferol (27), nevadensin (28), oroxylin A 7-O-glucuronide (29), quercetin (30), rosmarinic acid methyl ester (31), sakuranetin (32) and salvigenin (33).…”

“…New strategies such as the use of a multi‐components therapy in the hope to exploit synergic and/or additive effects, or the analyses of new and little explored new sources has been taken in consideration . Very recently some cyclic heptapseudopeptides have been synthetized taking paradoxically inspiration from a Staphylococcus aureus toxin, showing interesting activities against antibiotic‐resistant Gram ‐positive and ‐negative pathogens …”

“…[14][15][16] Very recently some cyclic heptapseudopeptides have been synthetized taking paradoxically inspiration from a Staphylococcus aureus toxin, showing interesting activities against antibioticresistant Gram-positive and -negative pathogens. [17] A further and promising tool for the development of the natural products and herbal extracts is the so called 'drug repurposing', which has been defined as the 'Studying the drugs that are already approved to treat one disease or condition to see if they are safe and effective for treating other diseases' as elaborated by the National Centre for Advancing Translational Sciences (NCATS, Bethesda, Maryland, USA) of the National Institute of Health (NIH, Bethesda, Maryland, USA). [18] This approach applied in these last years in the pharmaceutical sector has been mainly developed for economic reasons (but not only) because the production of a new drug is a very long (13-15 years) and very expensive (2-3 US$ billion) process, whereas the cost of a pharmaceutical repurposing of an old drug is about 300 million of US$, since in this case, the toxicity and clinical studies have been already carried out.…”

Experimental Evidence Reveals Both Cross-Infection and Cross-Contamination Risk of Embryo Storage in Liquid Nitrogen Biobanks

“…Over 90% of the bacteria isolated from seminal doses are resistant to common antibiotics added to extenders [55]. If this trend continues, the consequences for public health and the general community could be catastrophic [56]. To overcome this problem, the identification of therapeutic agents that can provide alternative treatments against conventional antibiotics are required.…”

A How-To Guide for Mode of Action Analysis of Antimicrobial Peptides

“…A classical method to examine bacterial morphology is transmission electron microscopy (TEM). TEM has been frequently employed to study antibiotic effects on bacterial cells, since it offers unique insight into bacterial ultrastructures (Friedrich et al, 2000;Sass et al, 2011;Nicolas et al, 2019;Vazquez-Muñoz et al, 2019). Sample preparation for TEM involves chemical fixation, dehydration, and contrasting with metal stains, followed by embedding in resin and ultrathin sectioning.…”