Synergistic Activity of Imipenem in Combination with Ceftazidime/Avibactam or Avibactam against Non-MBL-Producing Extensively Drug-Resistant Pseudomonas aeruginosa

Zhang, Yulin; Zhao, Jun; Han, Jiajing; Fan, Yanyan; Xiong, Zhujia; Zou, Xiaohui; Li, Binbin; Liu, Xinmeng; Li, Ziyao; Lu, Binghuai; Cao, Bin

doi:10.1128/spectrum.02740-21

Cited by 7 publications

(4 citation statements)

References 48 publications

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“…Growth curve was prepared using a previously described method with slight modification. 25 , 26 PAO1 culture was inoculated into 1 mL fresh LB broth at 37 °C with overnight shaking to reach the initial optical density of 0.01 at 600 nm (OD 600 ). Monitoring and recording the OD 600 of each sample was monitored and recorded using an enzyme marker to determine the growth density of culture for up to 36 h. Each experiment was performed using a sterile 96-well U-bottom polystyrene microtiter plate(Wuxi NEST Biotechnology Co., Ltd).…”

Section: Methodsmentioning

confidence: 99%

CRISPRi-Mediated Gene Suppression Reveals Putative Reverse Transcriptase Gene PA0715 to Be a Global Regulator of Pseudomonas aeruginosa

Zhou¹,

Huang²,

Xu³

et al. 2022

IDR

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Pseudomonas aeruginosa is a common pathogen of infection in burn and trauma patients, and multi-drug resistant P. aeruginosa has become an increasingly important pathogen. Essential genes are key to the development of novel antibiotics. The PA0715 gene is a novel unidentified essential gene that has attracted our interest as a potential antibiotic target. Our study aims to determine the exact role of PA0715 in cell physiology and bacterial pathogenicity, providing important clues for antibiotic development.Patients and Methods: The shuttle vector pHERD20T containing an arabinose inducible promoter was used to construct the CRISPRi system. Alterations in cellular physiology and bacterial pathogenicity of P. aeruginosa PAO1 after PA0715 inhibition were characterized. High-throughput RNA-seq was performed to gain more insight into the mechanisms by which PA0715 regulates the vital activity of P. aeruginosa. Results: We found that down-regulation of PA0715 significantly reduced PAO1 growth rate, motility and chemotaxis, antibiotic resistance, pyocyanin and biofilm production. In addition, PA0715 inhibition reduced the pathogenicity of PAO1 to the greater galleria mellonella larvae. Transcriptional profiling identified 1757 genes including those related to amino acid, carbohydrate, ketone body and organic salt metabolism, whose expression was directly or indirectly controlled by PA0715. Unexpectedly, genes involved in oxidative phosphorylation also varied with PA0715 levels, and these findings support a hitherto unrecognized critical role for PA0715 in oxidative respiration in P. aeruginosa. Conclusion:We identified PA0715 as a global regulator of the metabolic network that is indispensable for the survival and reproduction of P. aeruginosa. Our results provide a basis for future studies of potential antibiotic targets for P. aeruginosa and offer new ideas for P. aeruginosa infection control.

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Section: Methodsmentioning

confidence: 99%

CRISPRi-Mediated Gene Suppression Reveals Putative Reverse Transcriptase Gene PA0715 to Be a Global Regulator of Pseudomonas aeruginosa

Zhou¹,

Huang²,

Xu³

et al. 2022

IDR

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“…Zhang et al demonstrated the efficacy of CZA in combination with imipenem in the treatment of XDR- P. aeruginosa isolates that do not produce MBL but possess porin and AmpC mutations and multidrug efflux pumps and overexpress AmpC enzymes. Although counterintuitive, the efficacy of this combination may be explained by the reduction in the AmpC levels by ceftazidime, which acts as a suicide molecule, and by the inhibition of the AmpC enzymes by avibactam, in addition to the known reduced affinity of imipenem to efflux pumps [ 96 ].…”

Section: Antibiotic Synergy and Treatment Of Carbapenem-resistant Ent...mentioning

confidence: 99%

Antimicrobial and Diagnostic Stewardship of the Novel β-Lactam/β-Lactamase Inhibitors for Infections Due to Carbapenem-Resistant Enterobacterales Species and Pseudomonas aeruginosa

Ferous,

Anastassopoulou,

Pitiriga

et al. 2024

Antibiotics

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Carbapenem-resistant Gram-negative bacterial infections are a major public health threat due to the limited therapeutic options available. The introduction of the new β-lactam/β-lactamase inhibitors (BL/BLIs) has, however, altered the treatment options for such pathogens. Thus, four new BL/BLI combinations—namely, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam, and ceftolozane/tazobactam—have been approved for infections attributed to carbapenem-resistant Enterobacterales species and Pseudomonas aeruginosa. Nevertheless, although these antimicrobials are increasingly being used in place of other drugs such as polymyxins, their optimal clinical use is still challenging. Furthermore, there is evidence that resistance to these agents might be increasing, so urgent measures should be taken to ensure their continued effectiveness. Therefore, clinical laboratories play an important role in the judicious use of these new antimicrobial combinations by detecting and characterizing carbapenem resistance, resolving the presence and type of carbapenemase production, and accurately determining the minimum inhibitor concentrations (MICs) for BL/BLIs. These three targets must be met to ensure optimal BL/BLIs use and prevent unnecessary exposure that could lead to the development of resistance. At the same time, laboratories must ensure that results are interpreted in a timely manner to avoid delays in appropriate treatment that might be detrimental to patient safety. Thus, we herein present an overview of the indications and current applications of the new antimicrobial combinations and explore the diagnostic limitations regarding both carbapenem resistance detection and the interpretation of MIC results. Moreover, we suggest the use of alternative narrower-spectrum antibiotics based on susceptibility testing and present data regarding the effect of synergies between BL/BLIs and other antimicrobials. Finally, in order to address the absence of a standardized approach to using the novel BL/BLIs, we propose a diagnostic and therapeutic algorithm, which can be modified based on local epidemiological criteria. This framework could also be expanded to incorporate other new antimicrobials, such as cefiderocol, or currently unavailable BL/BLIs such as aztreonam/avibactam and cefepime/taniborbactam.

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“…In Pseudomonas aeruginosa, efflux pump overexpression and porin loss contribute to carbapenem resistance. Gram-negative bacteria are generally more resistant due to their cell wall, reduced permeability, efflux pumps, and broad-spectrum b-lactamases (Galani et al, 2021;Zhang et al, 2022). Some traditional treatments may be ineffective, highlighting the need for new antimicrobials to combat these resistant infections (Thaden et al, 2017).…”

Section: Pathogenesis Of Antibiotic Resistance In Carbapenem-resistan...mentioning

confidence: 99%

Transient comparison of techniques to counter multi-drug resistant bacteria: prime modules in curation of bacterial infections

Naveed,

Waseem,

Mahkdoom

et al. 2024

Front. Antibiot.

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Multidrug-resistant organisms are bacteria that are no longer controlled or killed by specific drugs. One of two methods causes bacteria multidrug resistance (MDR); first, these bacteria may disguise multiple cell genes coding for drug resistance to a single treatment on resistance (R) plasmids. Second, increased expression of genes coding for multidrug efflux pumps, which extrude many drugs, can cause MDR. Antibiotic resistance is a big issue since some bacteria may withstand almost all antibiotics. These bacteria can cause serious sickness, making them a public health threat. Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Multidrug resistant Mycobacterium tuberculosis (TB), and CRE are gut bacteria that resist antibiotics. Antimicrobial resistance is rising worldwide, increasing clinical and community morbidity and mortality. Superbugs have made antibiotic resistance in some environmental niches even harder to control. This study introduces new medicinal plants, gene-editing methods, nanomaterials, and bacterial vaccines that will fight MDR bacteria in the future.

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Synergistic Activity of Imipenem in Combination with Ceftazidime/Avibactam or Avibactam against Non-MBL-Producing Extensively Drug-Resistant Pseudomonas aeruginosa

Cited by 7 publications

References 48 publications

CRISPRi-Mediated Gene Suppression Reveals Putative Reverse Transcriptase Gene PA0715 to Be a Global Regulator of Pseudomonas aeruginosa

CRISPRi-Mediated Gene Suppression Reveals Putative Reverse Transcriptase Gene PA0715 to Be a Global Regulator of Pseudomonas aeruginosa

Antimicrobial and Diagnostic Stewardship of the Novel β-Lactam/β-Lactamase Inhibitors for Infections Due to Carbapenem-Resistant Enterobacterales Species and Pseudomonas aeruginosa

Transient comparison of techniques to counter multi-drug resistant bacteria: prime modules in curation of bacterial infections

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