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We are glad to share with you our first Journal Club and to highlight some of the most interesting papers published recently. We hope we will tease your curiosity and encourage you to read full papers outside of your research area, which you may not have read otherwise. The Biomolecules Scientific Board wishes you an exciting read.

Antibiotic resistance is a major public health challenge, and Gram-negative multidrug-resistant bacteria are particularly dangerous. The threat of running out of active molecules is accelerated by the extensive use of antibiotics in the context of the COVID-19 pandemic, and new antibiotics are urgently needed. Colistin and polymyxin B are natural antibiotics considered as last resort drugs for multi-resistant infections, but their use is limited because of neuro- and nephrotoxicity. We previously reported a series of synthetic analogues inspired in natural polymyxins with a flexible scaffold that allows multiple modifications to improve activity and reduce toxicity. In this work, we focus on modifications in the hydrophobic domains, describing analogues that broaden or narrow the spectrum of activity including both Gram-positive and Gram-negative bacteria, with MICs in the low µM range and low hemolytic activity. Using biophysical methods, we explore the interaction of the new molecules with model membranes that mimic the bacterial inner and outer membranes, finding a selective effect on anionic membranes and a mechanism of action based on the alteration of membrane function. Transmission electron microscopy observation confirms that polymyxin analogues kill microbial cells primarily by damaging membrane integrity. Redistribution of the hydrophobicity within the polymyxin molecule seems a plausible approach for the design and development of safer and more selective antibiotics.

There is a clear unmet medical need in the field of infectious diseases: infections caused by resistant bacteria. A major goal to fight resistant bacteria involves the design, discovery and development of new antibiotics particularly against multi-drug-resistant strains. Polymyxins, an old class of antimicrobial cyclic lipopeptides highly potent against therapeutically relevant Gram-negative bacteria, have been rescued and are now used only as last resort antibiotics in hospitals because of their nephrotoxicity and neurotoxicity that require careful monitoring of the patient. Our group has embarked in a project to design and develop new polymyxins devoid of toxicity problems using a versatile and chemically accessible scaffold structure[1,2]. Compounds show a remarkable activity against Gram-negative bacteria. Synergistic and antibiofilm activities have also been recently described in combination with imipenem[3]. Herein, the last results of our recently designed polymyxin analogs will be presented. References F. Rabanal, A. Grau-Campistany, X. Vila-Farres, J. Gonzalez-Linares, M. Borras, J. Vila, A. Manresa and Y. Cajal. A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity, Sci. Rep., 2015, 5, 10558. https://www.nature.com/articles/srep10558 F. Rabanal, Y. Cajal, Recent advances and perspectives in the design and development of polymyxins. Natural Product Reports, 34, 886 - 908 (2017) http://pubs.rsc.org/en/content/articlelanding/2017/np/c7np00023e#!divAbstract H. Rudilla, E. Fuste, Y. Cajal, F. Rabanal, T. Vinuesa and M. Vinas, Synergistic Antipseudomonal Effects of Synthetic Peptide AMP38 and Carbapenems, Molecules, 2016, 21, 1223. http://www.mdpi.com/1420-3049/21/9/1223

Antimicrobial peptides offer a new class of therapeutic agents to which bacteria may not be able to develop genetic resistance, since they act on the lipid component of the cell membranes [1]. [...]

The aim was to explore the antimicrobial activity of a synthetic peptide (AMP38) and its synergy with imipenem against imipenem-resistant Pseudomonas aeruginosa. The main mechanism of imipenem resistance is the loss or alteration of protein OprD. Time-kill and minimal biofilm eradication concentration (MBEC) determinations were carried out by using clinical imipenem-resistant strains. AMP38 was markedly synergistic with imipenem when determined in imipenem-resistant P. aeruginosa. MBEC obtained for the combination of AMP38 and imipenem was of 62.5 μg/mL, whereas the MBEC of each antimicrobial separately was 500 μg/mL. AMP38 should be regarded as a promising antimicrobial to fight MDR P. aeruginosa infections. Moreover, killing effect and antibiofilm activity of AMP38 plus imipenem was much higher than that of colistin plus imipenem.