Rapid selection of a cefiderocol-resistant<i>Escherichia coli</i>producing NDM-5 associated with a single amino acid substitution in the CirA siderophore receptor

Jousset, Agnès B; Poignon, Corentin; Yılmaz, Seher; Bleibtreu, Alexandre; Emeraud, Cécile; Girlich, Delphine; Naas, Thierry; Robert, Jérôme; Dortet, Laurent

doi:10.1093/jac/dkad004

Cited by 11 publications

(6 citation statements)

References 10 publications

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“…Comparing this strain with other genetically similar (equivalent sequence type, NDM-producing) cefiderocolsusceptible and cefiderocol-resistant CR E. coli strains, the authors suggested that a mutation in the cirA gene (via truncation and premature stop codon) was likely to be responsible for cefiderocol resistance [116]. Similar findings were reported on the role of NDM enzyme by Lan et al [117] and Jousset et al [118]. Previous work by Ito et al suggested that E. coli isolates with mutations in cirA and fiu genes resulted in a 16-fold increase in cefiderocol MIC values, although the isolates remained susceptible [92].…”

Section: Cefiderocol Resistance Mechanisms In Enterobacterales: On-th...supporting

confidence: 71%

Cefiderocol, a Siderophore Cephalosporin, as a Treatment Option for Infections Caused by Carbapenem-Resistant Enterobacterales

et al. 2023

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Carbapenem-resistant Enterobacterales (CRE) remain a significant public health threat, and, despite recent approvals, new antibiotics are needed. Severe infections caused by CRE, such as nosocomial pneumonia and bloodstream infections, are associated with a relatively high risk of morbidity and mortality. The recent approval of ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam, plazomicin, eravacycline and cefiderocol has broadened the armamentarium for the treatment of patients with CRE infections.Cefiderocol is a siderophore cephalosporin with overall potent in vitro activity against CRE. It is taken up via iron transport channels through active transport, with some entry into bacteria through traditional porin channels. Cefiderocol is relatively stable against hydrolysis by most serine-and metallo-beta-lactamases, including KPC, NDM, VIM, IMP and OXA carbapenemases-the most frequent carbapenemases detected in CRE. The efficacy and safety of cefiderocol has been demonstrated in three randomised, prospective, parallel group or controlled clinical studies in patients at risk of being infected by multidrug-resistant or carbapenem-resistant Gram-negative bacteria. This paper reviews the in vitro activity, emergence of resistance, preclinical effectiveness, and clinical experience for cefiderocol, and its role in the management of patients with CRE infections.

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Section: Cefiderocol Resistance Mechanisms In Enterobacterales: On-th...supporting

confidence: 71%

Cefiderocol, a Siderophore Cephalosporin, as a Treatment Option for Infections Caused by Carbapenem-Resistant Enterobacterales

et al. 2023

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“…In addition to the uptake of essential nutrients, TBDTs have been exploited for clinical antibiotic development, as exemplified by CirA in the uptake of cefiderocol. Concerningly, resistant strains can be acquired through mutations in CirA, − sometimes leading to fatal outcomes, emphasizing the need both for further antibiotic development and understanding of TBDTs.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial Lasso Peptide Cloacaenodin Utilizes a Unique TonB-Dependent Transporter to Access Susceptible Bacteria

Carson,

Juarez,

et al. 2024

ACS Chem. Biol.

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The development of new antimicrobial agents effective against Gramnegative bacteria remains a major challenge in drug discovery. The lasso peptide cloacaenodin has potent antimicrobial activity against multiple strains in the Enterobacter genus, one of the ESKAPE pathogens. Here, we show that cloacaenodin uses a previously uncharacterized TonB-dependent transporter, which we name CloU, to cross the outer membrane (OM) of susceptible bacteria. Inner membrane transport is mediated by the protein SbmA. CloU is distinct from the known OM transporters (FhuA and PupB) utilized by other antimicrobial lasso peptides and thus offers important insight into the spectrum of activity of cloacaenodin. Using knowledge of the transport pathway to predict other cloacaenodin-susceptible strains, we demonstrate the activity of cloacaenodin against clinical isolates of Enterobacter and of a Kluyvera strain. Further, we use molecular dynamics simulations and mutagenesis of CloU to explain the variation in cloacaenodin susceptibility observed across different strains of Enterobacter. This work expands the currently limited understanding of lasso peptide uptake and advances the potential of cloacaenodin as an antibiotic.

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“…The reemerged KPC/VIM producer had a high MIC for FDC because of the loss-of-function mutation in the CirA siderophore receptor. CirA mutations have previously been associated with FDC resistance in an in vitro model of New Delhi metallo-β-lactamase–producing K. pneumoniae ( 11 ) and in vivo for E. cloacae ( 14 ) and E. coli ( 15 ). However, the KPC/VIM–producing K. pneumoniae strain showed increased susceptibility to MVB, probably associated with a novel OmpK36 structure showing a large protein deletion; the 3-dimensional porin structure predicted a large lateral cave that might increase permeability of MVB.…”

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, cirA siderophore disruption substantially hinders bacterial fitness ( 13 ), and β-lactamase evolution contributing to FDC resistance typically comes at the price of functional trade-offs against other β-lactams ( 12 ). Under FDC treatment, in vivo resistance has been reported sporadically in Enterobacter cloacae ( 14 ) and Escherichia coli ( 15 ).…”

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confidence: 99%

Genotypic Evolution of Klebsiella pneumoniae Sequence Type 512 during Ceftazidime/Avibactam, Meropenem/Vaborbactam, and Cefiderocol Treatment, Italy

Arcari,

Cecilia,

Oliva

et al. 2023

Emerg. Infect. Dis.

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In February 2022, a critically ill patient colonized with a carbapenem-resistant K. pneumoniae producing KPC-3 and VIM-1 carbapenemases was hospitalized for SARS-CoV-2 in the intensive care unit of Policlinico Umberto I hospital in Rome, Italy. During 95 days of hospitalization, ceftazidime/avibactam, meropenem/vaborbactam, and cefiderocol were administered consecutively to treat 3 respiratory tract infections sustained by different bacterial agents. Those therapies altered the resistome of K. pneumoniae sequence type 512 colonizing or infecting the patient during the hospitalization period. In vivo evolution of the K. pneumoniae sequence type 512 resistome occurred through plasmid loss, outer membrane porin alteration, and a nonsense mutation in the cirA siderophore receptor gene, resulting in high levels of cefiderocol resistance. Cross-selection can occur between K. pneumoniae and treatments prescribed for other infective agents. K. pneumoniae can stably colonize a patient, and antimicrobial-selective pressure can promote progressive K. pneumoniae resistome evolution, indicating a substantial public health threat.

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Rapid selection of a cefiderocol-resistantEscherichia coliproducing NDM-5 associated with a single amino acid substitution in the CirA siderophore receptor

Cited by 11 publications

References 10 publications

Cefiderocol, a Siderophore Cephalosporin, as a Treatment Option for Infections Caused by Carbapenem-Resistant Enterobacterales

Cefiderocol, a Siderophore Cephalosporin, as a Treatment Option for Infections Caused by Carbapenem-Resistant Enterobacterales

Antimicrobial Lasso Peptide Cloacaenodin Utilizes a Unique TonB-Dependent Transporter to Access Susceptible Bacteria

Genotypic Evolution of Klebsiella pneumoniae Sequence Type 512 during Ceftazidime/Avibactam, Meropenem/Vaborbactam, and Cefiderocol Treatment, Italy

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