Structural Basis of PER-1-Mediated Cefiderocol Resistance and Synergistic Inhibition of PER-1 by Cefiderocol in Combination with Avibactam or Durlobactam in Acinetobacter baumannii

Liu, Xiaochen; Lei, Tailong; Yang, Yuan; Zhang, Linghong; Liu, Haiyang; Leptihn, Sebastian; Yu, Yunsong; Hua, Xiaoting

doi:10.1128/aac.00828-22

Cited by 10 publications

(15 citation statements)

References 24 publications

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“…Additionally, mutations in the baeSR genes were associated with reduced susceptibility of A. baumannii to cefiderocol by up-regulating the expression of the MFS family efflux pump and MacAB-TolC efflux pump (35). The modified expression of these genes seen in the studied heteroresistant cells, AMA22_1 IHCA, AMA23 IHC AVI, and AMA23 R AVI 8 μg/mL, could potentially be linked to the increased cefiderocol MIC seen in these strains.…”

Section: Modifications In the Transcript Levels Of Key Genes In The S...mentioning

confidence: 94%

Hetero-antagonism of avibactam and sulbactam with cefiderocol in carbapenem-resistantAcinetobacterspp

Wong,

Mezcord,

Lopez

et al. 2024

Preprint

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The emergence of Gram-negative bacteria resistant to multiple antibiotics, particularly carbapenem-resistant (CR)Acinetobacterstrains, poses a significant threat globally. Despite efforts to develop new antimicrobial therapies, limited progress has been made, with only two drugs—cefiderocol and sulbactam-durlobactam—showing promise for CR-Acinetobacterinfections. Cefiderocol, a siderophore cephalosporin, demonstrates promising efficacy in the treatment of Gram-negative infections. However, resistance to cefiderocol has been reported inA. baumannii. Combination therapies, such as cefiderocol with avibactam or sulbactam, show reduced MICs against cefiderocol-non-susceptible strains with in vivo efficacy, although the outcomes can be complex and species-specific. In the present work, the molecular characterization of spontaneous cefiderocol-resistant variants, a CRAB strain displaying antagonism with sulbactam and anA. lwoffiistrain showing antagonism with avibactam, were studied. The results reveal intriguing insights into the underlying mechanisms, including mutations affecting efflux pumps, transcriptional regulators, and iron homeostasis genes. Moreover, gene expression analysis reveals significant alterations in outer membrane proteins, iron homeostasis, and β-lactamases, suggesting adaptive responses to selective pressure. Understanding these mechanisms is crucial for optimizing treatment strategies and preventing adverse clinical outcomes. This study highlights the importance of preemptively assessing drug synergies to navigate the challenges posed by antimicrobial resistance in CR-Acinetobacterinfections.

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Section: Modifications In the Transcript Levels Of Key Genes In The S...mentioning

confidence: 94%

Hetero-antagonism of avibactam and sulbactam with cefiderocol in carbapenem-resistantAcinetobacterspp

Wong,

Mezcord,

Lopez

et al. 2024

Preprint

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“…Unfortunately, resistance to β-lactam-BLI combinations has been identified both in the laboratory and clinical settings, including against avibactam and vaborbactam, even before their approval by the FDA [25][26][27]. Recent studies have demonstrated antibiotic resistance against combination therapies involving the latest BLIs and against new β-lactams, such as durlobactam [28], relebactam [29,30], zidebactam [31], tazobactam [32], taniborbactam [33], thiol-containing BLIs under development [34], and cefiderocol [35]. The resistance mechanisms include upregulation of efflux, mutations in the β-lactam target PBPs, and expression of β-lactamases and mutants less susceptible to the specific BLI, such as KPC-109 [36], NDM-9 [33], IMP-6 [34], and CMY-178 [37].…”

Section: Targeting β-Lactamases: Innovative Technologies and Promisin...mentioning

confidence: 99%

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Jacobs,

Consol,

Chen

2024

Antibiotics

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β-Lactams are the most widely prescribed class of antibiotics that inhibit penicillin-binding proteins (PBPs), particularly transpeptidases that function in peptidoglycan synthesis. A major mechanism of antibiotic resistance is the production of β-lactamase enzymes, which are capable of hydrolyzing β-lactam antibiotics. There have been many efforts to counter increasing bacterial resistance against β-lactams. These studies have mainly focused on three areas: discovering novel inhibitors against β-lactamases, developing new β-lactams less susceptible to existing resistance mechanisms, and identifying non-β-lactam inhibitors against cell wall transpeptidases. Drug discovery in the β-lactam field has afforded a range of research opportunities for academia. In this review, we summarize the recent new findings on both β-lactamases and cell wall transpeptidases because these two groups of enzymes are evolutionarily and functionally connected. Many efforts to develop new β-lactams have aimed to inhibit both transpeptidases and β-lactamases, while several promising novel β-lactamase inhibitors have shown the potential to be further developed into transpeptidase inhibitors. In addition, the drug discovery progress against each group of enzymes is presented in three aspects: understanding the targets, screening methodology, and new inhibitor chemotypes. This is to offer insights into not only the advancement in this field but also the challenges, opportunities, and resources for future research. In particular, cyclic boronate compounds are now capable of inhibiting all classes of β-lactamases, while the diazabicyclooctane (DBO) series of small molecules has led to not only new β-lactamase inhibitors but potentially a new class of antibiotics by directly targeting PBPs. With the cautiously optimistic successes of a number of new β-lactamase inhibitor chemotypes and many questions remaining to be answered about the structure and function of cell wall transpeptidases, non-β-lactam transpeptidase inhibitors may usher in the next exciting phase of drug discovery in this field.

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“…Most MBLs and also some extended-spectrum beta-lactamases (ESBL) showed decreased susceptibility to CEFID [ 48 ]. A. baumannii can acquire CEFID resistance by producing the ESBL-type beta-lactamase PER-1, which is inactivated in vitro by adding avibactam or durlobactam [ 49 ]. Finally, a single resistance marker cannot predict non-susceptibility to CEFID, although combined mechanisms can [ 50 ].…”

Section: Recently Approved Antimicrobial Agentsmentioning

confidence: 99%

Novel Antimicrobial Agents for Gram-Negative Pathogens

et al. 2023

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Gram-negative bacterial resistance to antimicrobials has had an exponential increase at a global level during the last decades and represent an everyday challenge, especially for the hospital practice of our era. Concerted efforts from the researchers and the industry have recently provided several novel promising antimicrobials, resilient to various bacterial resistance mechanisms. There are new antimicrobials that became commercially available during the last five years, namely, cefiderocol, imipenem-cilastatin-relebactam, eravacycline, omadacycline, and plazomicin. Furthermore, other agents are in advanced development, having reached phase 3 clinical trials, namely, aztreonam-avibactam, cefepime-enmetazobactam, cefepime-taniborbactam, cefepime-zidebactam, sulopenem, tebipenem, and benapenem. In this present review, we critically discuss the characteristics of the above-mentioned antimicrobials, their pharmacokinetic/pharmacodynamic properties and the current clinical data.

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Structural Basis of PER-1-Mediated Cefiderocol Resistance and Synergistic Inhibition of PER-1 by Cefiderocol in Combination with Avibactam or Durlobactam in Acinetobacter baumannii

Abstract: Cefiderocol is a novel siderophore cephalosporin that displays activity against Gram-negative bacteria. To establish cefiderocol susceptibility levels of Acinetobacter baumannii strains from China, we performed susceptibility testing and genomic analyses on 131 clinical isolates.

Cited by 10 publications

References 24 publications

Hetero-antagonism of avibactam and sulbactam with cefiderocol in carbapenem-resistantAcinetobacterspp

Hetero-antagonism of avibactam and sulbactam with cefiderocol in carbapenem-resistantAcinetobacterspp

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Novel Antimicrobial Agents for Gram-Negative Pathogens

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