Abstract
Bacterial infections caused by antibiotic-resistant isolates have become a major health problem in recent years, since they are very difficult to treat, leading to an increase in morbidity and mortality. Fosfomycin is a broad-spectrum bactericidal antibiotic that inhibits cell wall biosynthesis in both Gram-negative and Gram-positive bacteria. This antibiotic has a unique mechanism of action and inhibits the initial step in peptidoglycan biosynthesis by blocking the enzyme, MurA. Fosfomycin has been used successfully for the treatment of urinary tract infections for a long time, but the increased emergence of antibiotic resistance has made fosfomycin a suitable candidate for the treatment of infections caused by multidrug-resistant pathogens, especially in combination with other therapeutic partners. The acquisition of fosfomycin resistance could threaten the reintroduction of this antibiotic for the treatment of bacterial infection. Here, we analyse the mechanism of action and molecular mechanisms for the development of fosfomycin resistance, including the modification of the antibiotic target, reduced antibiotic uptake and antibiotic inactivation. In addition, we describe the role of each pathway in clinical isolates.
Highlights
Infectious diseases are the second-major cause of death worldwide and the third-leading cause of death in economically advanced countries [1]
The crystal structure of E. coli MurA complexed with UDP-GlcNAc and fosfomycin has revealed that the Cys115-bound molecule is tightly packed between the enzyme and the substrate, forming strong electrostatic interactions between three conserved positively charged residues of MurA (Lys22, Arg120 and Arg397) and the phosphonate group of the antibiotic [16]
Fosfomycin has been used for a long time, but the emergence of antibiotic resistance and the decline in newly developed antibiotics has increased interest in the treatment of bacterial infections with this antibiotic
Summary
Infectious diseases are the second-major cause of death worldwide and the third-leading cause of death in economically advanced countries [1]. We focus our analysis on fosfomycin ( termed phosphomycin and phosphonomycin), a natural antibiotic compound produced by several Streptomyces and Pseudomonas species, exerting a powerful bactericidal activity against a wide range of Gram-negative and Gram-positive bacteria [4]. Fosfomycin is a phosphonic acid derivative containing an epoxide and a propyl group [(2R,3S-3-methyloxiran-2-yl) phosphonic acid] with a unique chemical structure (Figure 1). This molecule, with a very low molecular weight, is within a class of its own and is unrelated to any other antibiotic family, in addition to having an exclusive target, the initial step in peptidoglycan biosynthesis [5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
