Lubeluzole: from anti-ischemic drug to preclinical antidiarrheal studies
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ARTICLE
Lubeluzole: from anti‑ischemic drug to preclinical antidiarrheal studies Maria Maddalena Cavalluzzi1 · Roberta Budriesi2 · Maria Antonietta De Salvia3 · Laura Quintieri4 · Monica Piarulli1 · Gualtiero Milani1 · Roberta Gualdani5 · Matteo Micucci2 · Ivan Corazza6 · Antonio Rosato1 · Maurizio Viale7 · Leonardo Caputo4 · Carlo Franchini1 · Giovanni Lentini1 Received: 27 July 2020 / Revised: 21 September 2020 / Accepted: 25 September 2020 © Maj Institute of Pharmacology Polish Academy of Sciences 2020
Abstract Background Lubeluzole, a neuroprotective anti-ischemic drug, was tested for its ability to act as both antibiotic chemosensitizing and antipropulsive agent for the treatment of infectious diarrhea. Methods In the present report, the effect of lubeluzole against antidiarrheal target was tested. The antimicrobial activity towards Gram-positive and Gram-negative bacteria was investigated together with its ability to affect ileum and colon contractility. Results Concerning the antimicrobial activity, lubeluzole showed synergistic effects when used in combination with minocycline against four common Gram-positive and Gram-negative bacteria (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 29213, Pseudomonas aeruginosa ATCC 27853, and Escherichia coli ATCC 25922), although relatively high doses of lubeluzole were required. In ex vivo experiments on sections of gut smooth muscles, lubeluzole reduced the intestinal contractility in a dose-dependent manner, with greater effects observed on colon than on ileum, and being more potent than reference compounds otilonium bromide and loperamide. Conclusion All above results identify lubeluzole as a possible starting compound for the development of a novel class of antibacterial adjuvants endowed with spasmolytic activity. Graphic abstract
Keywords Lubeluzole · Diarrhoea · Ion channels · Antibiotics · Synergism · Gut contractility Electronic supplementary material The online version of this article (https://doi.org/10.1007/s43440-020-00167-2) contains supplementary material, which is available to authorized users. Extended author information available on the last page of the article
Abbreviations Ach Acetylcholine ATCC American Type Culture Collection BSCA Basal spontaneous contraction activity CaM Calmodulin
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CLSI Clinical and Laboratory Standard Institute CFU Colony forming units DMSO Dimethyl sulfoxide EFS Electrical field stimulation FIC Fractional inhibitory concentration FICI Fractional inhibitory concentration index FFT Fast Fourier transform GI Gastrointestinal hERG Human ether-à-go-go related gene MCA Mean contraction amplitude MDR Molecular drug resistance MH Muller Hinton MHB Mueller Hinton broth MICs Minimal inhibitory concentrations OB Otilonium bromide OD Optical density PSS Physiological salt solution SCV Spontaneous contraction variability SEM Standard error of the mean SC Spontaneous contractions SCV Spontaneous contraction variability UTHSCSA University of Texas Health Scien
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