A New Twist: The Combination of Sulbactam/Avibactam Enhances Sulbactam Activity against Carbapenem-Resistant Acinetobacter baumannii (CRAB) Isolates

Pasterán, Fernando; Cedano, José; Baez, Michelle; Albornoz, Ezequiel; Rapoport, Melina; Osteria, Jose; Montaña, Sabrina; Le, Casin; Ra, Grace; Tolmasky, Marcelo E.; Adams, Mark D.; Corso, Alejandra; Ramírez, María Soledad

doi:10.3390/antibiotics10050577

Cited by 11 publications

(16 citation statements)

References 42 publications

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“…Some of the knockout strains exhibited a fourfold decrease in the MIC in the sulbactam/zidebactam combination ( Table 2 ). Remarkably, when we compared with previously published results ( Pasteran et al., 2021 ), we observed loss of avibactam enhancement of sulbactam in this knockout strain (AB5075Δ mreB , AB5075 ΔadvA , AB5075 ΔadeB , AB5075 ΔPBPG ), suggesting that the sulbactam/zidebactam combination potentially possesses greater efficiency to inhibit these targets or recognize different target genes.…”

Section: Resultssupporting

confidence: 67%

“…However, against multidrug-resistant (MDR) A. baumannii isolates the efficacy of the current clinical combinations is uncertain. Novel experimental combinations such as sulbactam/avibactam demonstrated promising activity against CRAB with different genetic backgrounds; however, the combination was ineffective against MBL-expressing CRAB ( Rodriguez et al., 2020 ; Pasteran et al., 2021 ). Sulbactam/durlobactam (ETX2514) is also a promising combination in development that has shown very favorable activity against CRAB isolates, except in MBL producers ( Barnes et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Zidebactam restores sulbactam susceptibility against carbapenem-resistant Acinetobacter baumannii isolates

Cedano

Baez

Pasterán

et al. 2022

Front. Cell. Infect. Microbiol.

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Carbapenems are commonly used to treat infections caused by multidrug-resistant (MDR) bacteria. Unfortunately, carbapenem resistance is increasingly reported in many gram-negative bacteria, especially Acinetobacter baumannii. Diazabicyclooctane (DBO) β-lactamase inhibitors, such as avibactam (AVI), when combined with sulbactam successfully restore sulbactam susceptibility against certain carbapenem-resistant A. baumannii (CRAB) isolates. In the present study, we tested zidebactam, a novel DBO with an additional mechanism of action, in combination with sulbactam against CRAB isolates, including strains that exhibited resistance against sulbactam/avibactam combination. A panel of 43 geographically and genetically distinct CRAB isolates recovered from different hospitals and containing different mechanisms of resistance were included in the present study. We also tested three reference strains (AB0057, AB5075, and AYE). Minimum inhibitory concentrations (MICs) for sulbactam (range 0.12–512 mg/l) and sulbactam plus 4 mg/l zidebactam were performed using microdilution according to CLSI Standards. A decrease ≥2 dilutions in sulbactam MICs was observed in 84% of the isolates when tested in combination with zidebactam. The sulbactam/zidebactam combination was able to restore sulbactam susceptibility in 91% of the isolates, including isolates that were resistant to sulbactam/avibactam combination. These data encouraged us to further explore sulbactam/zidebactam in other experimental models especially against CRAB isolates resistant to other DBOs.

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Section: Resultssupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Zidebactam restores sulbactam susceptibility against carbapenem-resistant Acinetobacter baumannii isolates

Cedano

Baez

Pasterán

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Rodriguez CH et al [ 47 ] showed that avibactam at a fixed concentration of 4 mg/L reduced the MIC of sulbactam to ≤4 mg/L in all 35 non-metallo-β-lactamase (MBL)-producing sulbactam-resistant A. baumannii isolates in one study. The activity of sulbactam/avibactam (and to a lesser extent of sulbactam/relebactam) was also confirmed in a subsequent study [ 122 ]. The rationale of the combination is that avibactam may inhibit the β-lactamases that affect activity of sulbactam [ 47 ].…”

Section: Resultssupporting

confidence: 57%

“…The rationale of the combination is that avibactam may inhibit the β-lactamases that affect activity of sulbactam [ 47 ]. However, the combination is less effective against metallo-β-lactamase-producing isolates [ 47 , 122 ].…”

Section: Resultsmentioning

confidence: 99%

“…Such combinations may be even more active as triple combinations with polymyxins [ 51 , 61 , 69 , 82 ]. Furthermore, among non-polymyxin combinations, the recently proposed avibactam/sulbactam combination (aiming to restore susceptibility to sulbactam by inhibition of non-MBL β-lactamases with avibactam) is particularly promising and warrants further study [ 47 , 122 ].…”

Section: Discussionmentioning

confidence: 99%

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Systematic Review of Antimicrobial Combination Options for Pandrug-Resistant Acinetobacter baumannii

et al. 2021

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Antimicrobial combinations are at the moment the only potential treatment option for pandrug-resistant A. baumannii. A systematic review was conducted in PubMed and Scopus for studies reporting the activity of antimicrobial combinations against A. baumannii resistant to all components of the combination. The clinical relevance of synergistic combinations was assessed based on concentrations achieving synergy and PK/PD models. Eighty-four studies were retrieved including 818 eligible isolates. A variety of combinations (n = 141 double, n = 9 triple) were tested, with a variety of methods. Polymyxin-based combinations were the most studied, either as double or triple combinations with cell-wall acting agents (including sulbactam, carbapenems, glycopeptides), rifamycins and fosfomycin. Non-polymyxin combinations were predominantly based on rifampicin, fosfomycin, sulbactam and avibactam. Several combinations were synergistic at clinically relevant concentrations, while triple combinations appeared more active than the double ones. However, no combination was consistently synergistic against all strains tested. Notably, several studies reported synergy but at concentrations unlikely to be clinically relevant, or the concentration that synergy was observed was unclear. Selecting the most appropriate combinations is likely strain-specific and should be guided by in vitro synergy evaluation. Furthermore, there is an urgent need for clinical studies on the efficacy and safety of such combinations.

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Inhibitor Assessment against the LpxC Enzyme of Antibiotic‐resistant Acinetobacter baumannii Using Virtual Screening, Dynamics Simulation, and in vitro Assays

Zoghlami

Oueslati

Basharat

et al. 2022

Molecular Informatics

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Background: Bacterial resistance is currently a significant global public health problem. Acinetobacter baumannii has been ranked in the list of the World Health Organization as the most critical and priority pathogen for which new antibiotics are urgently needed. In this context, computational methods play a central role in the modern drug discovery process. The purpose of the current study was to identify new potential therapeutic molecules to neutralize MDR A. baumannii bacteria. Methods: A total of 3686 proteins retrieved from the A. baumannii proteome were subjected to subtractive proteomic analysis to narrow down the spectrum of drug targets. The SWISS-MODEL server was used to perform a 3D homology model of the selected target protein. The SAVES server was used to evaluate the overall quality of the model. A dataset of 74500 analogues retrieved from the PubChem database was docked with LpxC using the AutoDock software. Results: In this study, we predicted a putative new inhibitor for the Lpxc enzyme of A. baumannii. The LpxC enzyme was selected as the most appropriate drug target for A. baumannii. According to the virtual screening results, N-[(2S)-3amino-1-(hydroxyamino)-1-oxopropan-2-yl]-4-(4-bromophenyl) benzamide (CS250) could be a promising drug candidate targeting the LpxC enzyme. This molecule shows polar interactions with six amino acids and non-polar interactions with eight other residues. In vitro experimental validation was performed through the inhibition assay. Conclusion:To the best of our knowledge, this is the first study that suggests CS250 as a promising inhibitory molecule that can be exploited to target this gram-negative pathogen.

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A New Twist: The Combination of Sulbactam/Avibactam Enhances Sulbactam Activity against Carbapenem-Resistant Acinetobacter baumannii (CRAB) Isolates

Cited by 11 publications

References 42 publications

Zidebactam restores sulbactam susceptibility against carbapenem-resistant Acinetobacter baumannii isolates

Zidebactam restores sulbactam susceptibility against carbapenem-resistant Acinetobacter baumannii isolates

Systematic Review of Antimicrobial Combination Options for Pandrug-Resistant Acinetobacter baumannii

Inhibitor Assessment against the LpxC Enzyme of Antibiotic‐resistant Acinetobacter baumannii Using Virtual Screening, Dynamics Simulation, and in vitro Assays

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