In Vitro Antimicrobial Activity of a Siderophore Cephalosporin, S-649266, against Enterobacteriaceae Clinical Isolates, Including Carbapenem-Resistant Strains

Abstract

Enterobacter cloacae isolates were all <1 g/ml, and there were only 8 isolates (1.3%) among these 617 clinical isolates with MIC values of >8 g/ml. In the second set, the MIC values of S-649266 were <4 g/ml against 109 strains among 116 KPC-producing and class B (metallo) carbapenemase-producing strains. In addition, S-649266 showed MIC values of <2 g/ml against each of the 13 strains that produced other types of carbapenemases such as SME, NMC, and OXA-48. The mechanisms of the decreased susceptibility of 7 class B carbapenemase-producing strains with MIC values of >16 g/ml are uncertain. This is the first report to demonstrate that S-649266, a novel siderophore cephalosporin, has significant antimicrobial activity against Enterobacteriaceae, including strains that produce carbapenemases such as KPC and NDM-1.

Activity of the novel siderophore cephalosporin cefiderocol against multidrug-resistant Gram-negative pathogens

“…It possesses a unique mechanism for penetrating efficiently into Gram-negative pathogens. It uses a BTrojan horse^strategy by binding free iron and is then actively transported into bacterial cells across the outer membrane of Gram-negative bacteria by way of the iron-transport system [11,12]. Cefiderocol is a cephalosporin molecule with an attached catechol moiety on the 3-position side chain which binds to ferric iron [11].…”

“…It uses a BTrojan horse^strategy by binding free iron and is then actively transported into bacterial cells across the outer membrane of Gram-negative bacteria by way of the iron-transport system [11,12]. Cefiderocol is a cephalosporin molecule with an attached catechol moiety on the 3-position side chain which binds to ferric iron [11]. Once across the outer membrane, the iron dissociates and the cephalosporin binds to penicillin-binding proteins (PBP), mainly PBP3, as other cephalosporins do to disrupt cell wall synthesis [11,13], contributing to a potent antimicrobial activity against Gram-negative bacteria.…”

“…Cefiderocol is a cephalosporin molecule with an attached catechol moiety on the 3-position side chain which binds to ferric iron [11]. Once across the outer membrane, the iron dissociates and the cephalosporin binds to penicillin-binding proteins (PBP), mainly PBP3, as other cephalosporins do to disrupt cell wall synthesis [11,13], contributing to a potent antimicrobial activity against Gram-negative bacteria. In addition, this antimicrobial activity of cefiderocol is enhanced by the high stability of cefiderocol to hydrolysis by nearly all β-lactamases, including both the serine and metallo-carbapenemases [14].…”

β-Lactams and β-Lactamase Inhibitors: An Overview

“…Another recent addition to the cephalosporin family is the siderophore-substituted cephalosporin S-649266 with a catechol in the 3-position, thus allowing the molecule to enter the cells via an iron transport mechanism (Kohira et al 2015). In addition to increased penetrability, the cephalosporin is stable to hydrolysis by many carbapenemases, resulting in activity against many b-lactam-resistant enteric bacteria (Kohira et al 2015).…”

Structure and Function of the PiuA and PirA Siderophore-Drug Receptors from Pseudomonas aeruginosa and Acinetobacter baumannii

“…The iron-binding moiety of beta-lactam siderophore conjugates is frequently a small catechol-type siderophore, such as dihydroxypyridone or a mixed catechol-hydroxamate (7). Such conjugates have been developed with aminopenicillins (8), cephems (KP-736 and S-649266) (9)(10)(11), and monocyclic beta-lactams (pirazmonam, BAL30072, and MC-1) (12)(13)(14)(15). In particular, the monobactam conjugates show potent activity against the Gram-negative nonfermenters P. aeruginosa and A. baumannii (15)(16)(17)(18).…”