Platelets Inhibit Methicillin-Resistant Staphylococcus aureus by Inducing Hydroxyl Radical-Mediated Apoptosis-Like Cell Death

Liu, Erxiong; Chen, Yutong; Xu, Jing; Gu, Shunli; Xin, Jiajia; Wang, Wenting; Liu, Zhixin; An, Qing; Yi, Jun; Yin, Wen

doi:10.1128/spectrum.02441-21

Cited by 10 publications

(8 citation statements)

References 52 publications

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“…3N ). Increased expression of qoxC and qoxD suggests reduced electron supply to the oxidative respiratory chain, and the decreased expression of AZR indicates compromised electron supply to the oxidative respiratory chain ( 29 , 41 – 43 ) .These results provide evidence that K. pneumoniae suffered oxidative stress following platelet- K. pneumoniae coculture supernatant treatment.…”

Section: Resultsmentioning

confidence: 69%

“…Antibiotic treatment can induce cell apoptosis and cause the targeted cells to exhibit characteristic markers of apoptosis, including phosphatidylserine (PS) exposure, chromosome condensation, and DNA fragmentation ( 29 , 39 ). We found that the platelet- K. pneumoniae coculture supernatant had an antibiotic-like effect on K. pneumoniae in our previous study.…”

Section: Resultsmentioning

confidence: 99%

“…Previous reports have also revealed that antimicrobial peptides, such as cationic host defense peptides, contain positive charges and can bind to anionic bacterial membranes, causing lipid clustering and increasing membrane permeabilization ( 45 , 46 ), thereby inhibiting bacterial proliferation. In addition, combined treatment with NAC inhibits the antibacterial activities of daunomycin, moxifloxacin, and oxacillin against S. aureus ( 29 , 48 ). Our study supports the hypothesis that ROS play a key role in the supernatant-mediated apoptosis-like changes in K. pneumoniae .…”

Section: Discussionmentioning

confidence: 99%

“…Platelets directly induce DNA damage and the inhibition of S. aureus division ( 23 , 24 ). Platelets have also been shown to inhibit the growth of methicillin-resistant S. aureus by inducing hydroxyl radical-mediated apoptosis-like cell death ( 29 ). Meanwhile, the supernatant of platelets incubated with S. aureus has been reported to exert the same inhibitory effect as platelets do on the bacteria ( 30 ).…”

Section: Introductionmentioning

confidence: 99%

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Supernatant of platelet- Klebsiella pneumoniae coculture induces apoptosis-like death in Klebsiella pneumoniae

Wang,

Chen,

Chen

et al. 2024

Microbiol Spectr

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Multidrug-resistant Klebsiella pneumoniae strains, especially carbapenem-resistant K. pneumoniae , have become a rapidly emerging crisis worldwide, greatly limiting current therapeutic options and posing new challenges to infection management. Therefore, it is imperative to develop novel and effective biological agents for the treatment of multidrug-resistant K. pneumoniae infections. Platelets play an important role in the development of inflammation and immune responses. The main component responsible for platelet antibacterial activity lies in the supernatant stimulated by gram-positive bacteria. However, little research has been conducted on the interaction of gram-negative bacteria with platelets. Therefore, we aimed to explore the bacteriostatic effect of the supernatant derived from platelet- K. pneumoniae coculture and the mechanism underlying this effect to further assess the potential of platelet-bacterial coculture supernatant. We conducted this study on the gram-negative bacteria K. pneumoniae and CRKP and detected turbidity changes in K. pneumoniae and CRKP cultures when grown with platelet- K. pneumoniae coculture supernatant added to the culture medium. We found that platelet- K. pneumoniae coculture supernatant significantly inhibited the growth of K. pneumoniae and CRKP in vitro . Furthermore, transfusion of platelet- K. pneumoniae coculture supernatant alleviated the symptoms of K. pneumoniae and CRKP infection in a murine model. Additionally, we observed apoptosis-like changes, such as phosphatidylserine exposure, chromosome condensation, DNA fragmentation, and overproduction of reactive oxygen species in K. pneumoniae following treatment with the supernatant. Our study demonstrates that the platelet- K. pneumoniae coculture supernatant can inhibit K. pneumoniae growth by inducing an apoptosis-like death, which is important for the antibacterial strategies development in the future. IMPORTANCE With the widespread use of antibiotics, bacterial resistance is increasing, and a variety of multi-drug resistant Gram-negative bacteria have emerged, which brings great challenges to the treatment of infections caused by Gram-negative bacteria. Therefore, finding new strategies to inhibit Gram-negative bacteria and even multi-drug- resistant Gram-negative bacteria is crucial for treating infections caused by Gram-negative bacteria, improving the abuse of antibiotics, and maintaining the balance between bacteria and antibiotics. K. pneumoniae is a common clinical pathogen, and drug-resistant CRKP is increasingly difficult to cure, which brings great clinical challenges. In this study, we found that the platelet- K. pneumoniae coculture supernatant can inhibit K. pneumoniae growth by inducing an apoptosis-like death. This finding has inspired the development of future antimicrobial strategies, which are expected to improve the clinical treatment of Gram-negative bacteria and control the development of multidrug-resistant strains.

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Section: Resultsmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Supernatant of platelet- Klebsiella pneumoniae coculture induces apoptosis-like death in Klebsiella pneumoniae

Wang,

Chen,

Chen

et al. 2024

Microbiol Spectr

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“…Moreover, a study by Dwyer et al [70] found that bacteria, like eukaryotic cells, possess mechanisms of apoptotic-like death (ALD) under specific stimulation, such as platelets, beetroot extract, and chitooligosaccharides. [71][72][73] Meanwhile, P5CDH plays an important role in cell death. [74] Interestingly, our study revealed that the inhibition of P5CDH activity by celastrol would induce ALD through the accumulation of P5C, which may subsequently lead to cell death.…”

Section: Discussionmentioning

confidence: 99%

Celastrol Combats Methicillin‐Resistant Staphylococcus aureus by Targeting Δ¹‐Pyrroline‐5‐Carboxylate Dehydrogenase

Yuan

Wang

et al. 2023

Advanced Science

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The emergence and rapid spread of methicillin‐resistant Staphylococcus aureus (MRSA) raise a critical need for alternative therapeutic options. New antibacterial drugs and targets are required to combat MRSA‐associated infections. Based on this study, celastrol, a natural product from the roots of Tripterygium wilfordii Hook. f., effectively combats MRSA in vitro and in vivo. Multi‐omics analysis suggests that the molecular mechanism of action of celastrol may be related to Δ1‐pyrroline‐5‐carboxylate dehydrogenase (P5CDH). By comparing the properties of wild‐type and rocA‐deficient MRSA strains, it is demonstrated that P5CDH, the second enzyme of the proline catabolism pathway, is a tentative new target for antibacterial agents. Using molecular docking, bio‐layer interferometry, and enzyme activity assays, it is confirmed that celastrol can affect the function of P5CDH. Furthermore, it is found through site‐directed protein mutagenesis that the Lys205 and Glu208 residues are key for celastrol binding to P5CDH. Finally, mechanistic studies show that celastrol induces oxidative stress and inhibits DNA synthesis by binding to P5CDH. The findings of this study indicate that celastrol is a promising lead compound and validate P5CDH as a potential target for the development of novel drugs against MRSA.

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The Combination of Membrane Disruption and FtsZ Targeting by a Chemotherapeutic Hydrogel Synergistically Combats Pathogens Infections

Wei,

Guo,

Geng

et al. 2024

Adv Healthcare Materials

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The emergence of multidrug‐resistant (MDR) bacteria poses a significant challenge to global health. Due to a shortage of antibiotics, alternative therapeutic strategies are urgently needed. Unfortunately, colistin, the last‐resort antibiotic, has unavoidable nephrotoxicity and hepatotoxicity, and its single killing mechanism is prone to drug resistance. To address this challenge, we propose a promising combinatorial approach that includes colistin, a membrane‐disrupting antimicrobial agent, and chelerythrine (CHE), a FtsZ protein inhibitor. This approach significantly reduces antibiotic dose and development of resistance, leading to almost complete inactivation of MDR pathogens in vitro. To address solubility issues and ensure transport, we used the antimicrobial hydrogel system LNP‐CHE‐CST@hydrogel, which induced reactive oxygen species (ROS) and apoptosis‐like cell death by targeting the FtsZ protein. In an in vivo mouse skin infection model, the combination therapy effectively eliminated MDR bacteria within 24 hours, as monitored by fluorescence tracking. Our findings demonstrate a promising approach for developing multifunctional hydrogels to combat MDR bacterial infections.This article is protected by copyright. All rights reserved

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Platelets Inhibit Methicillin-Resistant Staphylococcus aureus by Inducing Hydroxyl Radical-Mediated Apoptosis-Like Cell Death

Abstract: The widespread use of antibiotics has led to the emergence of drug-resistant bacteria, particularly multidrug-resistant bacteria. MRSA is the most common drug-resistant bacterium that causes suppurative infections in humans.

Cited by 10 publications

References 52 publications

Supernatant of platelet- Klebsiella pneumoniae coculture induces apoptosis-like death in Klebsiella pneumoniae

Supernatant of platelet- Klebsiella pneumoniae coculture induces apoptosis-like death in Klebsiella pneumoniae

Celastrol Combats Methicillin‐Resistant Staphylococcus aureus by Targeting Δ¹‐Pyrroline‐5‐Carboxylate Dehydrogenase

The Combination of Membrane Disruption and FtsZ Targeting by a Chemotherapeutic Hydrogel Synergistically Combats Pathogens Infections

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Platelets Inhibit Methicillin-Resistant Staphylococcus aureus by Inducing Hydroxyl Radical-Mediated Apoptosis-Like Cell Death

Abstract: The widespread use of antibiotics has led to the emergence of drug-resistant bacteria, particularly multidrug-resistant bacteria. MRSA is the most common drug-resistant bacterium that causes suppurative infections in humans.

Cited by 10 publications

References 52 publications

Supernatant of platelet- Klebsiella pneumoniae coculture induces apoptosis-like death in Klebsiella pneumoniae

Supernatant of platelet- Klebsiella pneumoniae coculture induces apoptosis-like death in Klebsiella pneumoniae

Celastrol Combats Methicillin‐Resistant Staphylococcus aureus by Targeting Δ1‐Pyrroline‐5‐Carboxylate Dehydrogenase

The Combination of Membrane Disruption and FtsZ Targeting by a Chemotherapeutic Hydrogel Synergistically Combats Pathogens Infections

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Product

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About

Celastrol Combats Methicillin‐Resistant Staphylococcus aureus by Targeting Δ¹‐Pyrroline‐5‐Carboxylate Dehydrogenase