Antibiotic susceptibility signatures identify potential antimicrobial targets in the Acinetobacter baumannii cell envelope

Geisinger, Edward; Mortman, Nadav J.; Dai, Yunfei; Çokol, Murat; Syal, Sapna; Farinha, Andrew; Fisher, Delaney G.; Tang, Amy Y.; Lazinski, David W.; Wood, Stephen; Anthony, Jon; Opijnen, Tim van; Isberg, Ralph R.

doi:10.1038/s41467-020-18301-2

Cited by 85 publications

(179 citation statements)

References 87 publications

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“…advA (antibiotic susceptibility and division protein of Acinetobacter ) is another essential gene for A. baumannii growth. It has been shown that reduced AdvA levels modulated antibiotic susceptibility and generate a selective pattern of hypersensitivity to fluoroquinolones and β-lactams [ 38 ]. Avibactam could be a hypothetical mediator for sulbactam hypersensitivity through advA interaction.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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An increasing number of untreatable infections are recorded every year. Many studies have focused their efforts on developing new β-lactamase inhibitors to treat multi-drug resistant (MDR) isolates. In the present study, sulbactam/avibactam and sulbactam/relebactam combination were tested against 187 multi-drug resistant (MDR) Acinetobacter clinical isolates; both sulbactam/avibactam and sulbactam/relebactam restored sulbactam activity. A decrease ≥2 dilutions in sulbactam MICs was observed in 89% of the isolates when tested in combination with avibactam. Sulbactam/relebactam was able to restore sulbactam susceptibility in 40% of the isolates. In addition, the susceptibility testing using twenty-three A. baumannii AB5075 knockout strains revealed potential sulbactam and/or sulbactam/avibactam target genes. We observed that diazabicyclooctanes (DBOs) β-lactamase inhibitors combined with sulbactam restore sulbactam susceptibility against carbapenem-resistant Acinetobacter clinical isolates. However, relebactam was not as effective as avibactam when combined with sulbactam. Exploring novel combinations may offer new options to treat Acinetobacter spp. infections, especially for widespread oxacillinases and metallo-β-lactamases (MBLs) producers.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…Tn-seq can be applied for the identification of genes required for resistance to bactericides ( Lai et al, 2017 ; Vitale et al, 2020 ) and potential antimicrobial target genes. For instance, the potential targets of multiple antibiotics were identified in the Acinetobacter baumannii via Tn-seq ( Geisinger et al, 2020 ). R. solanacearum is probably the most destructive plant pathogenic bacterium worldwide ( Mansfield et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Bacterial ClpP Protease Is a Potential Target for Methyl Gallate

Zheng

Yuan

et al. 2021

Front. Microbiol.

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Methyl gallate (MG) is an effective microbicide with great potential application in the integrated management of plant diseases and an important potential drug for clinical application. However, its target remains unknown. This study conducted a transposon sequencing (Tn-seq) under MG treatment in plant pathogenic bacterium Ralstonia solanacearum. Tn-seq identified that the mutation of caseinolytic protease proteolytic subunit gene clpP significantly increased the resistance of R. solanacearum to MG, which was validated by the in-frame gene deletion. iTRAQ (isobaric tags for relative and absolute quantitation) proteomics analysis revealed that chemotaxis and flagella associated proteins were the major substrates degraded by ClpP under the tested condition. Moreover, sulfur metabolism-associated proteins were potential substrates of ClpP and were upregulated by MG treatment in wild-type R. solanacearum but not in clpP mutant. Furthermore, molecular docking confirmed the possible interaction between MG and ClpP. Collectively, this study revealed that MG might target bacterial ClpP, inhibit the activity of ClpP, and consequently disturb bacterial proteostasis, providing a theoretical basis for the application of MG.

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“…It is associated with major health concerns in different regions of the world. These infections are responsible for about 1.5 million cases yearly (3,4).…”

Section: Introductionmentioning

confidence: 99%

Phenotypic and Genotypic Evaluation of Antibiotic Resistance of Acinetobacter baumannii Bacteria Isolated from Surgical Intensive Care Unit Patients in Pakistan

Zahra

Zeshan

Qadri

et al. 2021

Jundishapur J Microbiol

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Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a significant nosocomial pathogen, causing serious threats concerning community-wide outbreaks globally, as well as in Pakistan. Antimicrobial resistance in A. baumannii is increasing day by day. Objectives: The study aimed to find out the antibiotic resistance (AMR) patterns and evaluate the AMR genes in clinical isolates from patients admitted to the surgical Intensive Care units (ICUs) at different hospitals in Lahore, Pakistan. Methods: A total of 593 clinical specimens were collected from patients admitted to the surgical ICUs of three different local hospitals in Lahore, Pakistan. From these samples, a total of 90 A. baumannii isolates were identified and further investigated to observe phenotypic resistance patterns and detect carbapenemases resistance genes. Results: The results showed that phenotypic resistance against amikacin was 27.2%, ceftriaxone 100%, ceftazidime 27.2%, cefepime 63.3%, ciprofloxacin and co-trimoxazole 100%, gentamicin 40%, imipenem 22.2%, meropenem 21.1%, piperacillin-tazobactam 27.2%, tigecycline 27.2%, and tetracycline 63.3%. All A. baumannii isolates were found to be sensitive to colistin (CT), polymixin-B (PB), and tobramycin (TOB). The PCR amplification of carbapenemases genes revealed the prevalence of blaOXA-23, blaOXA-51, and blaOXA-40 in 73, 90, and 64.4% of the isolates, respectively, along with blaNDM1 (92.2%), blaVIM (40%), blaIMP (90%), ISAba1 (85.5%), sul1 (16.6%), sul2 (20%), armA (32.2%), and PER-1 (12%) while the blaOXA-24 and blaOXA-58 genes were not detected in the isolates. The sequence analysis of the blaOXA-23 and blaOXA-51 genes showed 98% and 95% similarity with previously reported sequences in the GenBank database. Conclusions: The present study indicated that the emergence of high carbapenem resistance in CRAB isolates has increased, which may pose serious limitations in the choice of drugs for nosocomial infections.

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Antibiotic susceptibility signatures identify potential antimicrobial targets in the Acinetobacter baumannii cell envelope

Cited by 85 publications

References 87 publications

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

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

Bacterial ClpP Protease Is a Potential Target for Methyl Gallate

Phenotypic and Genotypic Evaluation of Antibiotic Resistance of Acinetobacter baumannii Bacteria Isolated from Surgical Intensive Care Unit Patients in Pakistan

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