Contents lists available at ScienceDirect Gene Reports journal homepage: www.elsevier.com/locate/genrep Fosfomycin: A look at its various aspects Sahar Tajik a , Fazlollah Shokri b , Mostafa Rostamnezhad c , Saeed Khoshnood d , Seyed Mojtaba Mortazavi d , Mohammad Sholeh e , Ebrahim Kouhsari f,g, ⁎ a Department of Endodontics, Faculty of Dentistry, Islamic Azad University, Khorasgan (Isfahan) Branch, Isfahan, Iran b Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran c Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran d Student Research Committee, School of Medicine, Bam University of Medical Sciences, Bam, Iran e Department of Microbiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran f Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran g Laboratory Sciences Research Center, Golestan University of Medical Sciences, Gorgan, Iran ARTICLE INFO Keywords: Antibiotic resistance Fosfomycin Antibacterial activity Mechanisms of resistance ABSTRACT Today, due to the emergence and spread of multidrug-resistant bacteria that have caused many therapeutic problems for the medical systems, and the lack of production of effective antibiotics in the commercial field in recent years, physicians are increasingly interested in using older antibiotics such as fosfomycin. Besides, be- cause of the relatively low bacterial resistance to fosfomycin and its broad spectrum of action, it seems to be a molecule of therapeutic interest in the era of infection treatment. This antibiotic is still effective against many multidrug-resistant and extensively drug-resistant bacteria by inhibiting the early stages of the cell wall as- sembly. In this review, we summarize the currently available data regarding pharmacokinetics and pharmaco- dynamics, mechanism of action, oral and parenteral use, susceptibility breakpoints, antibacterial activity, me- chanisms and epidemiology of resistance, and adverse effects of fosfomycin. 1. Introduction The crisis spread in multidrug-resistant (MDR) or extensively drug- resistant (XDR) bacterial pathogens lead to appealing therapeutic op- tions (Neuner et al., 2012; Falagas et al., 2010a). The effectiveness of fosfomycin as useful option treatments against MDR bacteria was al- ready evaluated in in vitro and clinical settings (Neuner et al., 2012; Falagas et al., 2010a). Historically, the first fosfomycin (also called phosphomycin or phosphonomycin) introduced in 1969 in Spain and originally isolated from cultures of the Streptomyces spp. (Falagas et al., 2010a; Aghamali et al., 2018). Fosfomycin has an exclusive chemical structure and no cross-re- sistance with other known classes of antimicrobial agents (Falagas et al., 2016). Additionally, the elimination of fosfomycin through the kidney leads to a high urine concentration for > 24 h that supports the use of fosfomycin for the treatment of urinary tract infections (UTIs) (Kandil et al., 2016; Baylan, 2010). Over time, it has a broad range activity against MDR Gram-negative and Gram-positive bacteria, which irreversibly blocking the first step of bacterial cell wall peptidoglycan biosynthesis by inhibiting phosphoenolpyruvate (PEP) transferase (acts as the first and essential enzyme in the synthesis of peptidoglycan) (Falagas et al., 2016; Castañeda-García et al., 2013). Up to now, three molecular mechanisms that impaired drug uptake and lead to fosfomycin resistance, also described (Aghamali et al., 2018). With this background, we summarized the primary fosfomycin data available as a proven and valuable choice for the prophylactic or treatment of deep-seated or difficult to treat infections. 2. Chemical structure Fosfomycin ([(2R,3S)-3-methyloxiran-2-yl] phosphonic acid), is a small molecular weight (138.059 Da), hydrophilic, low toxic, and un- ique chemical structure molecule with negligible serum protein-binding tendency, that deprived of nitrogen moieties (Aghamali et al., 2018; https://doi.org/10.1016/j.genrep.2020.100640 Received 25 November 2019; Received in revised form 3 March 2020; Accepted 4 March 2020 Abbreviations: PCR, polymerase chain reaction; MDR, multidrug-resistant; XDR, extensively drug-resistant; UTIs, urinary tract infections; PEP, phosphoenolpyr- uvate; CSF, cerebral spinal fluid; GlpT, L-a-glycerol-3-phosphate transport system; UhpT, hexose–phosphate uptake transport system; cAMP-CRP, cyclic adenosine monophosphate-receptor protein complex; EUCAST, European Committee on Antimicrobial Susceptibility Testing; CLSI, Clinical and Laboratory Standards Institute's; ESBL, Extended-spectrum beta-lactamases ⁎ Corresponding author at: Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran. E-mail address: Kouhsari-E@Medilam.ac.ir (E. Kouhsari). Gene Reports 19 (2020) 100640 Available online 05 March 2020 2452-0144/ © 2020 Published by Elsevier Inc. T