A Potential Nontraditional Approach To Combat
            <i>tmexCD1-toprJ1-</i>
            Mediated Tigecycline Resistance: Melatonin as a Synergistic Adjuvant of Tigecycline

Wang, Xiaoming; Liu, Ting; Lv, Xi; Sun, Naiyan; Li, Fan; Luo, Lei; Zhuge, Xiangkai; Huang, Jinhu; Wang, Liping

doi:10.1128/aac.00047-23

Cited by 4 publications

(3 citation statements)

References 36 publications

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“…In this sense, the more persuasive studies are those showing that MLT-deficient animals have higher susceptibility and/or higher mortality when infected with influenza virus H1N1 [ 78 ], Leishmania amazonensis [ 103 ] and Toxoplasma gondii [ 107 ]. Other outstanding studies are those showing that MLT may overcome tigecycline resistance in a model of Klebsiella pneumoniae infection [ 88 ], as well as its synergy with amphotericin B in combating Visceral Leishmaniases [ 105 ]. These observations suggest that combining MLT with antiviral drugs or antibiotics might be a very promising approach for fighting infections.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, the transferable resistance–nodulation–division efflux pump TMexCD1-TOprJ1, conferring resistance to tigecycline, is becoming a serious health problem. A potentially very interesting and novel approach for combatting resistance to tigecycline used MLT, either in vitro or in vivo, in an infection model using tmexCD1-toprJ1 -positive Klepsiella pneumoniae with encouraging results [ 88 ]. However, even in this study, MLT was used at extremely high concentrations (2–8 mg/mL) and doses (50 mg/kg) [ 88 ].…”

Section: Mlt and Bacterial Infectionsmentioning

confidence: 99%

“…A potentially very interesting and novel approach for combatting resistance to tigecycline used MLT, either in vitro or in vivo, in an infection model using tmexCD1-toprJ1 -positive Klepsiella pneumoniae with encouraging results [ 88 ]. However, even in this study, MLT was used at extremely high concentrations (2–8 mg/mL) and doses (50 mg/kg) [ 88 ]. Table 2 lists the preclinical in vivo studies of the effects of MLT on bacterial infections.…”

Section: Mlt and Bacterial Infectionsmentioning

confidence: 99%

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Role of Melatonin in Viral, Bacterial and Parasitic Infections

Maestroni

2024

Biomolecules

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In all mammals, the circulating pool of MLTs is synthesized in the pineal gland during the night’s darkness hours. Its main function is synchronizing the organism in the photoperiod. In contrast, extra-pineal MLT is synthesized in peripheral organs, does not follow any circadian rhythm or circulate, and plays a detoxifying and cytoprotective role. Circulating MLT may stimulate both innate and acquired immune responses through its circadian action and by activating high-affinity receptors on immunocompetent cells. Extra-pineal MLT may have antioxidant and anti-inflammatory effects that dampen the innate immune response. These two seemingly divergent roles may be considered to be two sides of the same coin. In fact, the integration of both circulating and extra-pineal MLT functions might generate a balanced and effective immune response against microbial pathogens. The studies described in this review investigated the effects of exogenous MLT in various models of infectious diseases using extremely different doses and treatment schedules. None of them evaluated the possibility of integrating the non-circadian anti-inflammatory effect with the circadian immunoenhancing action of MLT. As a consequence, in spite of the fact that most studies agree that MLT has a beneficial effect against infections, it seems difficult to draw any definite conclusion about its possible therapeutic use.

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Section: Discussionmentioning

confidence: 99%

Section: Mlt and Bacterial Infectionsmentioning

confidence: 99%

Section: Mlt and Bacterial Infectionsmentioning

confidence: 99%

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Role of Melatonin in Viral, Bacterial and Parasitic Infections

Maestroni

2024

Biomolecules

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Exploiting membrane vesicles derived from avian pathogenic Escherichia coli as a cross-protective subunit vaccine candidate against avian colibacillosis

Zhu,

Zhang,

Wang

et al. 2024

Poultry Science

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Repurposing harmaline as a novel approach to reverse tmexCD1-toprJ1-mediated tigecycline resistance against klebsiella pneumoniae infections

Yang#,

Xu#,

Zhou

et al. 2024

Microb Cell Fact

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Background A novel plasmid-mediated resistance–nodulation–division (RND) efflux pump gene cluster tmexCD1-toprJ1 in Klebsiella pneumoniae tremendously threatens the use of convenient therapeutic options in the post-antibiotic era, including the “last-resort” antibiotic tigecycline. Results In this work, the natural alkaloid harmaline was found to potentiate tigecycline efficacy (4- to 32-fold) against tmexCD1-toprJ1-positive K. pneumoniae, which also thwarted the evolution of tigecycline resistance. Galleria mellonella and mouse infection models in vivo further revealed that harmaline is a promising candidate to reverse tigecycline resistance. Inspiringly, harmaline works synergistically with tigecycline by undermining tmexCD1-toprJ1-mediated multidrug resistance efflux pump function via interactions with TMexCD1-TOprJ1 active residues and dissipation of the proton motive force (PMF), and triggers a vicious cycle of disrupting cell membrane integrity and metabolic homeostasis imbalance. Conclusion These results reveal the potential of harmaline as a novel tigecycline adjuvant to combat hypervirulent K. pneumoniae infections.

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A Potential Nontraditional Approach To Combat tmexCD1-toprJ1- Mediated Tigecycline Resistance: Melatonin as a Synergistic Adjuvant of Tigecycline

Cited by 4 publications

References 36 publications

Role of Melatonin in Viral, Bacterial and Parasitic Infections

Role of Melatonin in Viral, Bacterial and Parasitic Infections

Exploiting membrane vesicles derived from avian pathogenic Escherichia coli as a cross-protective subunit vaccine candidate against avian colibacillosis

Repurposing harmaline as a novel approach to reverse tmexCD1-toprJ1-mediated tigecycline resistance against klebsiella pneumoniae infections

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