Combined With Mefloquine, Resurrect Colistin Active in Colistin-Resistant Pseudomonas aeruginosa in vitro and in vivo

Zhang, Xiaodong; Zhao, Yiting; Feng, Luozhu; Xu, Mengxin; Ge, Yiru; Wang, Lingbo; Zhang, Ying; Cao, Jianming; Sun, Yao; Wu, Qing; Zhou, Tieli

doi:10.3389/fmicb.2021.790220

Cited by 10 publications

(8 citation statements)

References 33 publications

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“…Furthermore, the combination of mefloquine-colistin might also reduce the expression of the QS system, thereby inhibiting biofilm formation. 27 In our present study, the combination of mefloquine and AS101 exhibited a significant reduction in CRPA-5 and CRPA-6 biofilms. We postulate that this effect is potentially attributed to the notable increase in bacterial cell membrane permeability and enhanced drug influx during concurrent administration.…”

supporting

confidence: 58%

“…According to reported literature, the antimalarial drug mefloquine has demonstrated the ability to significantly enhance antibacterial activity when utilized in combination with other antibacterial agents, such as colistin and antituberculosis drugs. 26,27 Based on this premise, the study employed a combination of AS101 and mefloquine for the treatment of CRPA. The chessboard assay showed that when AS101 and mefloquine were combined, the MIC of the two drugs decreased by 4-8 times.…”

Section: Discussionmentioning

confidence: 99%

“…For example, mefloquine might enhance the activity of colistin against colistin-resistant Enterobacter and P. aeruginosa. 26,27 In addition to common antibiotics, mefloquine possesses a synergistic effect on inhibitory drugs and improves the efficacy of anti-tuberculosis drugs such as isoniazid, pyrazinamide, and fluoroquinolones. 28 Thus, we postulate that the combination of AS101 with mefloquine may enhance the antibacterial activity through synergistic effect.…”

Section: Introductionmentioning

confidence: 99%

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Combination of AS101 and Mefloquine Inhibits Carbapenem-Resistant Pseudomonas aeruginosa in vitro and in vivo

Li,

Shen,

et al. 2023

IDR

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In recent years, carbapenem-resistant Pseudomonas aeruginosa (CRPA) has spread around the world, leading to a high mortality and close attention of medical community. In this study, we aim to find a new strategy of treatment for CRPA infections. Methods: Eight strains of CRPA were collected, and PCR detected the multi-locus sequence typing (MLST). The antimicrobial susceptibility test was conducted using the VITEK@2 compact system. The minimum inhibitory concentration (MIC) for AS101 and mefloquine was determined using the broth dilution method. Antibacterial activity was tested in vitro and in vivo through the chessboard assay, time killing assay, and a mouse model. The mechanism of AS101 combined with mefloquine against CRPA was assessed through the biofilm formation inhibition assay, electron microscopy, and detection of reactive oxygen species (ROS). Results:The results demonstrated that all tested CRPA strains exhibited multidrug resistance. Moreover, our investigation revealed a substantial synergistic antibacterial effect of AS101-mefloquine in vitro. The assay for inhibiting biofilm formation indicated that AS101-mefloquine effectively suppressed the biofilm formation of CRPA-5 and CRPA-6. Furthermore, AS101-mefloquine were observed to disrupt the bacterial cell wall and enhance the permeability of the cell membrane. This effect was achieved by stimulating the production of ROS, which in turn hindered the growth of CRPA-3. To evaluate the therapeutic potential, a murine model of CRPA-3 peritoneal infection was established. Notably, AS101-mefloquine administration resulted in a significant reduction in bacterial load within the liver, kidney, and spleen of mice after 72 hours of treatment. Conclusion:The present study showed that the combination of AS101 and mefloquine yielded a notable synergistic bacteriostatic effect both in vitro and in vivo, suggesting a potential clinical application of this combination in the treatment of CRPA.

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supporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combination of AS101 and Mefloquine Inhibits Carbapenem-Resistant Pseudomonas aeruginosa in vitro and in vivo

Li,

Shen,

et al. 2023

IDR

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“…The biofilm inhibitory effect of NG combined with colistin was further investigated by scanning electron microscopy (SEM) ( Zhang et al, 2021b ). Reference experiments were performed with simple modifications.…”

Section: Methodsmentioning

confidence: 99%

Naringenin restores colistin activation against colistin-resistant gram-negative bacteria in vitro and in vivo

Yao²,

Zhao³

et al. 2022

Front. Microbiol.

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Colistin is used as the “last line of defense” against multidrug-resistant (MDR) Gram-negative bacteria (GNB). However, improper use of colistin may further lead to an increasing number of colistin-resistant (Col-R) strains worldwide, which greatly limits antibiotic treatment options. In this study, we investigated the antibacterial and antibiofilm activities of naringenin (NG) combined with colistin against Col-R GNB in vitro and in vivo. The checkerboard method and time-kill test showed that NG combined with colistin has better antibacterial activity (FICI < 0.5) compared with NG and colistin alone. Biofilm formation inhibition tests demonstrated that combining the two drugs could inhibit biofilm formation; scanning electron microscopy (SEM) confirmed that the combination of the two significantly reduces the number of cells in the biofilm compared with the drug alone. The in vivo experiment showed that the combination of NG and colistin can improve the survival rate of the Galleria mellonella (G. mellonella) and reduce the microbial load in the mouse thigh infection model. Mechanistically, the combination of NG and colistin synergistically enhances the antibacterial activity and changes the permeability of the bacterial outer membrane. More importantly, cytotoxicity tests showed no cell cytotoxicity of NG in combination with colistin. In conclusion, our data revealed that NG combined with colistin exhibited good synergistic effects in vivo and in vitro, thus providing a new therapeutic option for clinical Col-R GNB infections.

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“…Besides our study, antimalarials, except for TAF, have demonstrated diverse antimicrobial activities. For example, artemisinin and its derivatives, mefloquine, and chloroquine have been reported to exhibit antibacterial or antifungal effects ( 19 , 42 – 44 ). A series of primaquine derivatives have been shown broad-spectrum antimicrobial activity ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

Repurposing of the antimalarial agent tafenoquine to combat MRSA

She,

Yang,

et al. 2023

mSystems

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Staphylococcus aureus is an important human pathogen that often leads to hospital-acquired and community-acquired infections. The appearance of methicillin-resistant S. aureus (MRSA) has made the treatment extremely challenging. There is an urgent need to develop new antimicrobial agents to combat MRSA infections. In this study, through high-throughput screening, we found that tafenoquine (TAF), an antimalarial agent, exhibited antimicrobial efficacy against MRSA and its highly resistant phenotypes of biofilm and persister cells. No resistant mutation emerged by consecutive sub-minimal inhibitory concentration of TAF induction. Mechanistic studies by fluorescent probes of SYTOX Green/DiSC3(5), molecular dynamic simulations, electron microscopy, and proteomic analysis revealed that TAF exerts antimicrobial activity mainly through selective bacterial cell membrane disruption. In addition, TAF exhibited an effective antimicrobial effect in a subcutaneous abscess model in vivo with a good toxicity profile. In conclusion, TAF may have the potential to be developed as a new antimicrobial agent to treat refractory MRSA infections. IMPORTANCE This study represents the first investigation into the antimicrobial effect of TAF against S. aureus and its potential mechanisms. Our data highlighted the effects of TAF against MRSA planktonic cells, biofilms, and persister cells, which is conducive to broadening the application of TAF. Through mechanistic studies, we revealed that TAF targets bacterial cell membranes. In addition, the in vivo experiments in mice demonstrated the safety and antimicrobial efficacy of TAF, suggesting that TAF could be a potential antibacterial drug candidate for the treatment of infections caused by multiple drug-resistant S. aureus .

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Combined With Mefloquine, Resurrect Colistin Active in Colistin-Resistant Pseudomonas aeruginosa in vitro and in vivo

Cited by 10 publications

References 33 publications

Combination of AS101 and Mefloquine Inhibits Carbapenem-Resistant Pseudomonas aeruginosa in vitro and in vivo

Combination of AS101 and Mefloquine Inhibits Carbapenem-Resistant Pseudomonas aeruginosa in vitro and in vivo

Naringenin restores colistin activation against colistin-resistant gram-negative bacteria in vitro and in vivo

Repurposing of the antimalarial agent tafenoquine to combat MRSA

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