When Combined with Pentamidine, Originally Ineffective Linezolid Becomes Active in Carbapenem-Resistant Enterobacteriaceae

Tang, Miran; Qian, Changrui; Zhang, Xiaotuan; Liu, Yan; Pan, Wei; Yao, Zhuocheng; Zeng, Weiliang; Xu, Chunyan; Zhou, Tieli

doi:10.1128/spectrum.03138-22

Cited by 7 publications

(4 citation statements)

References 28 publications

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“…Previous work by our group had shown the potentiation of linezolid by pentamidine in CRE, including carbapenem-resistant E. coli , K. pneumoniae , and E. cloacae clinical isolates [ 7 ]. Xinxin Feng et al also verified that pentamidine and linezolid have a highly synergistic effect against E. coli [ 14 ].…”

Section: Resultsmentioning

confidence: 99%

“…The combination of pentamidine and rifampicin was reported to show potent in vitro activity against carbapenem- and/or colistin-resistant Enterobacteriaceae bacteria [ 6 ]. We also observed that combining pentamidine and linezolid had significant synergistic antibacterial and anti-biofilm activity, as well as in vivo efficacy in the clinical isolation of carbapenem-resistant enterobacteria (CRE) [ 7 ]. However, the properties of drugs that can be combined with pentamidine and the mechanisms of their synergistic antibacterial activity are still not completely understood.…”

Section: Introductionmentioning

confidence: 99%

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The Properties of Linezolid, Rifampicin, and Vancomycin, as Well as the Mechanism of Action of Pentamidine, Determine Their Synergy against Gram-Negative Bacteria

Tang,

Zhao,

Liu

et al. 2023

IJMS

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Combining pentamidine with Gram-positive-targeting antibiotics has been proven to be a promising strategy for treating infections from Gram-negative bacteria (GNB). However, which antibiotics pentamidine can and cannot synergize with and the reasons for the differences are unclear. This study aimed to identify the possible mechanisms for the differences in the synergy of pentamidine with rifampicin, linezolid, tetracycline, erythromycin, and vancomycin against GNB. Checkerboard assays were used to detect the synergy of pentamidine and the different antibiotics. To determine the mechanism of pentamidine, fluorescent labeling assays were used to measure membrane permeability, membrane potential, efflux pump activity, and reactive oxygen species (ROS); the LPS neutralization assay was used to evaluate the target site; and quantitative PCR was used to measure changes in efflux pump gene expression. Our results revealed that pentamidine strongly synergized with rifampicin, linezolid, and tetracycline and moderately synergized with erythromycin, but did not synergize with vancomycin against E. coli, K. pneumoniae, E. cloacae, and A. baumannii. Pentamidine increased the outer membrane permeability but did not demolish the outer and inner membranes, which exclusively permits the passage of hydrophobic, small-molecule antibiotics while hindering the entry of hydrophilic, large-molecule vancomycin. It dissipated the membrane proton motive force and inactivated the efflux pump, allowing the intracellular accumulation of antimicrobials that function as substrates of the efflux pump, such as linezolid. These processes resulted in metabolic perturbation and ROS production which ultimately was able to destroy the bacteria. These mechanisms of action of pentamidine on GNB indicate that it is prone to potentiating hydrophobic, small-molecule antibiotics, such as rifampicin, linezolid, and tetracycline, but not hydrophilic, large-molecule antibiotics like vancomycin against GNB. Collectively, our results highlight the importance of the physicochemical properties of antibiotics and the specific mechanisms of action of pentamidine for the synergy of pentamidine–antibiotic combinations. Pentamidine engages in various pathways in its interactions with GNB, but these mechanisms determine its specific synergistic effects with certain antibiotics against GNB. Pentamidine is a promising adjuvant, and we can optimize drug compatibility by considering its functional mechanisms.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Properties of Linezolid, Rifampicin, and Vancomycin, as Well as the Mechanism of Action of Pentamidine, Determine Their Synergy against Gram-Negative Bacteria

Tang,

Zhao,

Liu

et al. 2023

IJMS

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“…The synergy between colistin and azomycin was evaluated through a time-killing assay, as previously described . Briefly, overnight cultures of the nine COL-R ECC strains were standardized to a 0.5 McFarland standard using NS and introduced into 20 mL of fresh broth and subjected to azomycin, colistin, or azomycin–colistin; a negative control was maintained with the broth alone.…”

Section: Methodsmentioning

confidence: 99%

Azomycin Orchestrate Colistin-Resistant Enterobacter cloacae Complex’s Colistin Resistance Reversal In Vitro and In Vivo

Hu,

Chen,

Zhao

et al. 2024

ACS Infect. Dis.

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The Enterobacter cloacae complex (ECC) is a group of nosocomial pathogens that pose a challenge in clinical treatment due to its intrinsic resistance and the ability to rapidly acquire resistance. Colistin was reconsidered as a last-resort antibiotic for combating multidrug-resistant ECC. However, the persistent emergence of colistin-resistant (COL-R) pathogens impedes its clinical efficacy, and novel treatment options are urgently needed. We propose that azomycin, in combination with colistin, restores the susceptibility of COL-R ECC to colistin in vivo and in vitro. Results from the checkerboard susceptibility, time-killing, and live/dead bacterial cell viability tests showed strong synergistic antibacterial activity in vitro. Animal infection models suggested that azomycin−colistin enhanced the survival rate of infected Galleria mellonella and reduced the bacterial load in the thighs of infected mice, highlighting its superior in vivo synergistic antibacterial activity. Crystal violet staining and scanning electron microscopy unveiled the in vitro synergistic antibiofilm effects of azomycin−colistin. The safety of azomycin and azomycin−colistin at experimental concentrations was confirmed through cytotoxicity tests and an erythrocyte hemolysis test. Azomycin−colistin stimulated the production of reactive oxygen species in COL-R ECC and inhibited the PhoPQ two-component system to combat bacterial growth. Thus, azomycin is feasible as a colistin adjuvant against COL-R ECC infection.

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“…In addition to these modification strategies, the combination of oxazolidinones with adjuvants, like efflux pump inhibitors and outer membrane permeabilizers, may represent an alternative approach to enhance or reinstate the efficacy of existing antibiotics, including oxazolidinone drugs against MDR strains. − For instance, the dipeptide phenylalanine-arginine-β-naphthylamide could inhibit resistance–nodulation–cell division (RND) efflux pumps, resulting in improving or restoring the activity of different ribosomal antibiotics. , Polymyxin, as an outer membrane permeabilizer, is also used to enhance the antibacterial activity of antibiotics. , Pentamidine, as an outer membrane permeabilizer and efflux pump inhibitor, enables the initially ineffective linezolid to become effective against the problematic carbapenem-resistant Enterobacteriaceae (CRE) both in vitro and in vivo , exhibiting excellent synergistic antibacterial and anti-membranous effects, as well as potential application prospects in the treatment of CRE-associated infections …”

Section: Outlook and Future Perspectivesmentioning

confidence: 99%

Strategies for the Discovery of Oxazolidinone Antibacterial Agents: Development and Future Perspectives

Liu,

Jiang,

Jiao

et al. 2023

J. Med. Chem.

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Oxazolidinones represent a significant class of synthetic bacterial protein synthesis inhibitors that are primarily effective against Gram-positive bacteria. The commercial success of linezolid, the first FDA-approved oxazolidinone antibiotic, has motivated researchers to develop more potent oxazolidinones by employing various drug development strategies to fight against antimicrobial resistance, some of which have shown promising results. Thus, this Perspective aims to discuss the strategies employed in constructing oxazolidinone-based antibacterial agents and summarize recent advances in discovering oxazolidinone antibiotics to provide valuable insights for potentially developing next-generation oxazolidinone antibacterial agents or other pharmaceuticals.

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When Combined with Pentamidine, Originally Ineffective Linezolid Becomes Active in Carbapenem-Resistant Enterobacteriaceae

Abstract: The multidrug resistance and biofilm formation of Gram-negative bacteria (GNB) may lead to incurable “superbug” infections. Drug combinations, with the potential to augment the original treatment ranges of drugs, are alternative treatment strategies against GNB.

Cited by 7 publications

References 28 publications

The Properties of Linezolid, Rifampicin, and Vancomycin, as Well as the Mechanism of Action of Pentamidine, Determine Their Synergy against Gram-Negative Bacteria

The Properties of Linezolid, Rifampicin, and Vancomycin, as Well as the Mechanism of Action of Pentamidine, Determine Their Synergy against Gram-Negative Bacteria

Azomycin Orchestrate Colistin-Resistant Enterobacter cloacae Complex’s Colistin Resistance Reversal In Vitro and In Vivo

Strategies for the Discovery of Oxazolidinone Antibacterial Agents: Development and Future Perspectives

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