Poly(2‐Oxazoline)‐Based Functional Peptide Mimics: Eradicating MRSA Infections and Persisters while Alleviating Antimicrobial Resistance

Zhou, Min; Qian, Yuxin; Xie, Jiayang; Zhang, Wenjing; Jiang, Weinan; Xiao, Ximian; Chen, Sheng; Dai, Chengzhi; Cong, Zihao; Ji, Zhemin; Shao, Ning; Liu, Longqiang; Wu, Yuequn; Liu, Runhui

doi:10.1002/ange.202000505

Cited by 19 publications

(23 citation statements)

References 80 publications

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“…The increase in the ROS level might be due to greater cytosolic stress caused by the complementary functional mechanisms of polymer (binding with nucleic acids) and rifampicin (inhibition of nucleic acid synthesis). DNA binding by antimicrobial polymers was also observed by Zhou et al [47] to cause strong SOS response, leading to elevation of intracellular ROS level. [48] The rapid production of ROS implies a final effector role in bacterial cell death following treatment with polymer/rifampicin combination.…”

Section: Mechanistic Studymentioning

confidence: 64%

A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics

et al. 2020

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In order to mitigate antibiotic resistance, a new strategy to increase antibiotic potency and reverse drug resistance is needed. Herein, the translocation mechanism of an antimicrobial guanidinium‐functionalized polycarbonate is leveraged in combination with traditional antibiotics to afford a potent treatment for drug‐resistant bacteria. Particularly, this polymer–antibiotic combination approach reverses rifampicin resistance phenotype in Acinetobacter baumannii demonstrating a 2.5 × 105‐fold reduction in minimum inhibitory concentration (MIC) and a 4096‐fold reduction in minimum bactericidal concentration (MBC). This approach also enables the repurposing of auranofin as an antibiotic against multidrug‐resistant (MDR) Gram‐negative bacteria with a 512‐fold MIC and 128‐fold MBC reduction, respectively. Finally, the in vivo efficacy of polymer–rifampicin combination is demonstrated in a MDR bacteremia mouse model. This combination approach lays foundational ground rules for a new class of antibiotic adjuvants capable of reversing drug resistance phenotype and repurposing drugs against MDR Gram‐negative bacteria.

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Section: Mechanistic Studymentioning

confidence: 64%

A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics

et al. 2020

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“…This suggested that an increase in the concentration of peptide resulted in an enhancement of ROS production, which indirectly affected the growth of S. aureus ATCC 25923. However, it is known that if the bacterial cells fail to minimize the excess of intracellular ROS production, membrane depolarization occurs, which ultimately leads to cell death ( Yadav et al, 2020 ; Zhou et al, 2020 ). The same phenomenon was observed in our study.…”

Section: Resultsmentioning

confidence: 99%

Deciphering the Antibacterial Role of Peptide From Bacillus subtilis subsp. spizizenii Ba49 Against Staphylococcus aureus

et al. 2021

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An increase in antibiotic resistance has led to escalating the need for the development of alternate therapy. Antimicrobial peptides (AMPs) are at the forefront of replacing conventional antibiotics, showing slower development of drug resistance, antibiofilm activity, and the ability to modulate the host immune response. The ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens that jeopardize most conventional antibiotics are known to be involved in severe respiratory tract, bloodstream, urinary tract, soft tissue, and skin infections. Among them, S. aureus is an insidious microbe and developed resistance against conventional antibiotics. In the present study, an AMP (named as peptide-Ba49) isolated from Bacillus subtilis subsp. spizizenii strain from Allium cepa (the common onion) exhibited strong antibacterial efficacy against S. aureus ATCC 25923. The mode of action of this peptide-Ba49 on S. aureus was deciphered through various sensitive probes, i.e., DiSC3 (5) and H2DCFDA, suggesting the peptide-Ba49 to be acting upon through change in membrane potential and by triggering the production of reactive oxygen species (ROS). This induced disruption of the cell membrane was further supported by morphological studies using scanning electron microscopy (SEM). Investigations on a possible post-antibiotic effect (PAE) of peptide-Ba49 showed prolonged PAE against S. aureus. Furthermore, the peptide-Ba49 prevented the formation of S. aureus biofilm at low concentration and showed its potential to degrade the mature biofilm of S. aureus. The peptide-Ba49 also exhibited intracellular killing potential against S. aureus ATCC 25923 in the macrophage cells, and moreover, peptide-Ba49 was found to bolster the fibroblast cell migration in the scratch assay at low concentration, exhibiting a wound healing efficacy of this peptide. These studies demonstrated that peptide-Ba49 isolated from the strain B. subtilis subsp. spizizenii could be a therapeutic candidate to combat the pathogenic S. aureus infections.

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“…Bithionol (10 μg/ml) was used as control. The fluorescence intensity was measured at the excitation wavelength of 622 nm with emission wavelength of 670 nm ( Zhou et al, 2020 ). The experiments were repeated in triplicate.…”

Section: Methodsmentioning

confidence: 99%

Repurposing Candesartan Cilexetil as Antibacterial Agent for MRSA Infection

She

Chen

et al. 2021

Front. Microbiol.

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Staphylococcus aureus is an important pathogen causing hospital-acquired infections. Methicillin-resistant S. aureus (MRSA), biofilms, and persisters are highly tolerant to traditional antibiotics and make it difficult to treat. Therefore, new antimicrobial agents are urgently needed to treat hard-to-eradicate diseases caused by this bacterium. In this study, candesartan cilexetil (CC), an angiotensin hypertension drug, had strong antimicrobial activity against S. aureus with minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of 8–16 μg/ml and 16–32 μg/ml. CC exhibited limited cytotoxicity and low potential to induce drug resistance. In addition, it showed a synergistic antibacterial effect when combined with gentamicin and tobramycin. The effective concentrations to inhibit MRSA biofilm formation were 16–64 μg/ml, and intractable persisters were killed at 4–8 × MIC. Through the analysis of its mechanism of action, it was evident that the membrane permeability was disrupted as well as the cell structure was damaged. Furthermore, we demonstrated that CC had antibacterial effects in vivo in MRSA-infected murine skin abscess models. In conclusion, these results imply that CC might be a potential antibacterial agent for the treatment of S. aureus-associated infections.

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Poly(2‐Oxazoline)‐Based Functional Peptide Mimics: Eradicating MRSA Infections and Persisters while Alleviating Antimicrobial Resistance

Cited by 19 publications

References 80 publications

A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics

A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics

Deciphering the Antibacterial Role of Peptide From Bacillus subtilis subsp. spizizenii Ba49 Against Staphylococcus aureus

Repurposing Candesartan Cilexetil as Antibacterial Agent for MRSA Infection

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