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L-lysine potentiates aminoglycosides against Acinetobacter baumannii via regulation of proton motive force and antibiotics uptake.

ABSTRACT: Acinetobacter baumannii, a Gram-negative opportunistic pathogen, is a leading cause of hospital- and community-acquired infections. Acinetobacter baumannii can rapidly acquire diverse resistance mechanisms and undergo genetic modifications that confer resistance and persistence to all currently used clinical antibiotics. In this study, we found exogenous L-lysine sensitizes Acinetobacter baumannii, other Gram-negative bacteria (Escherichia coli and Klebsiella pneumoniae) and a Gram-positive bacterium (Mycobacterium smegmatis) to aminoglycosides. Importantly, the combination of L-lysine with aminoglycosides killed clinically isolated multidrug-resistant Acinetobacter baumannii and persister cells. The exogenous L-lysine can increase proton motive force via transmembrane chemical gradient, resulting in aminoglycoside acumination that further accounts for reactive oxygen species production. The combination of L-lysine and antibiotics highlights a promising strategy against bacterial infection.

SUBMITTER: Deng W

PROVIDER: S-EPMC7144275 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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L-lysine potentiates aminoglycosides against Acinetobacter baumannii via regulation of proton motive force and antibiotics uptake.

Deng Wanyan W Fu Tiwei T Zhang Zhen Z Jiang Xiao X Xie Jianping J Sun Hang H Hu Peng P Ren Hong H Zhou Peifu P Liu Qi Q Long Quanxin Q

Emerging microbes & infections 20200320 1

Acinetobacter baumannii, a Gram-negative opportunistic pathogen, is a leading cause of hospital- and community-acquired infections. Acinetobacter baumannii can rapidly acquire diverse resistance mechanisms and undergo genetic modifications that confer resistance and persistence to all currently used clinical antibiotics. In this study, we found exogenous L-lysine sensitizes Acinetobacter baumannii, other Gram-negative bacteria (Escherichia coli and Klebsiella pneum ...[more]

PMID: 32192413

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Project description:BackgroundThe global rise in multidrug-resistant bacteria has significantly undermined the efficacy of traditional antibiotics. Multidrug-resistant Streptococcus suis (S. suis), a pathogen capable of infecting pigs and humans, has been identified as a critical threat, causing severe meningitis and rapid mortality. In response, researchers have increasingly focused on herbal compounds as non-traditional antimicrobial agents, which can inhibit bacterial growth while minimizing the risk of resistance development. This study investigates the mechanism through which andrographolide (AP) restores the susceptibility of S. suis to aminoglycoside antibiotics.MethodsThe intracellular ΔpH in S. suis was assessed using the 2',7' -bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCCF-AM) probe to evaluate alterations in the proton motive force (PMF) following treatment with AP. Non-targeted metabolomics was employed to confirm changes in the metabolic profile of S. suis upon exposure to AP. Finally, an in vivo infection model was utilized to evaluate the therapeutic efficacy of AP in combination with antibiotics.ResultsExtensive in vitro experiments demonstrated that AP significantly enhances the activity of aminoglycoside antibiotics against diverse pathogens, including S. suis. Further studies revealed that bacterial death results from AP-mediated upregulation of the S. suis PMF, which enhances cellular uptake of tobramycin (TOB). Moreover, AP significantly upregulated pyruvate metabolism in S. suis, accelerated the tricarboxylic acid (TCA) cycle, and increased nicotinamide adenine dinucleotide (NADH) production. This metabolic shift further augmented the PMF. Combining AP with aminoglycoside antibiotics significantly reduced bacterial load and organ lesions in various organs in mice.ConclusionAP holds promise as an adjuvant to aminoglycoside antibiotics for combating S. suis-induced infections, offering a theoretical foundation for clinical applications.

Project description:Antibiotic susceptibility of bacterial pathogens is typically evaluated using in vitro assays that do not consider the complex host microenvironment. This may help explaining a significant discrepancy between antibiotic efficacy in vitro and in vivo, with some antibiotics being effective in vitro but not in vivo or vice versa. Nevertheless, it is well-known that antibiotic susceptibility of bacteria is driven by environmental factors. Lung epithelial cells enhance the activity of aminoglycoside antibiotics against the opportunistic pathogen Pseudomonas aeruginosa, yet the mechanism behind is unknown. The present study addresses this gap and provides mechanistic understanding on how lung epithelial cells stimulate aminoglycoside activity. To investigate the influence of the local host microenvironment on antibiotic activity, an in vivo-like three-dimensional (3-D) lung epithelial cell model was used. We report that conditioned medium of 3-D lung cells, containing secreted but not cellular components, potentiated the bactericidal activity of aminoglycosides against P. aeruginosa, including resistant clinical isolates, and several other pathogens. In contrast, conditioned medium obtained from the same cell type, but grown as conventional (2-D) monolayers did not influence antibiotic efficacy. We found that 3-D lung cells secreted endogenous metabolites (including succinate and glutamate) that enhanced aminoglycoside activity, and provide evidence that bacterial pyruvate metabolism is linked to the observed potentiation of antimicrobial activity. Biochemical and phenotypic assays indicated that 3-D cell conditioned medium stimulated the proton motive force (PMF), resulting in increased bacterial intracellular pH. The latter stimulated antibiotic uptake, as determined using fluorescently labelled tobramycin in combination with flow cytometry analysis. Our findings reveal a cross-talk between host and bacterial metabolic pathways, that influence downstream activity of antibiotics. Understanding the underlying basis of the discrepancy between the activity of antibiotics in vitro and in vivo may lead to improved diagnostic approaches and pave the way towards novel means to stimulate antibiotic activity.

Project description:There is considerable interest in improving plant productivity by altering the dynamic responses of photosynthesis in tune with natural conditions. This is exemplified by the 'energy-dependent' form of non-photochemical quenching (qE), the formation and decay of which can be considerably slower than natural light fluctuations, limiting photochemical yield. In addition, we recently reported that rapidly fluctuating light can produce field recombination-induced photodamage (FRIP), where large spikes in electric field across the thylakoid membrane (Δψ) induce photosystem II recombination reactions that produce damaging singlet oxygen (1O2). Both qE and FRIP are directly linked to the thylakoid proton motive force (pmf), and in particular, the slow kinetics of partitioning pmf into its ΔpH and Δψ components. Using a series of computational simulations, we explored the possibility of 'hacking' pmf partitioning as a target for improving photosynthesis. Under a range of illumination conditions, increasing the rate of counter-ion fluxes across the thylakoid membrane should lead to more rapid dissipation of Δψ and formation of ΔpH. This would result in increased rates for the formation and decay of qE while resulting in a more rapid decline in the amplitudes of Δψ-spikes and decreasing 1O2 production. These results suggest that ion fluxes may be a viable target for plant breeding or engineering. However, these changes also induce transient, but substantial mismatches in the ATP : NADPH output ratio as well as in the osmotic balance between the lumen and stroma, either of which may explain why evolution has not already accelerated thylakoid ion fluxes. Overall, though the model is simplified, it recapitulates many of the responses seen in vivo, while spotlighting critical aspects of the complex interactions between pmf components and photosynthetic processes. By making the programme available, we hope to enable the community of photosynthesis researchers to further explore and test specific hypotheses.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'.

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L-lysine potentiates aminoglycosides against Acinetobacter baumannii via regulation of proton motive force and antibiotics uptake.

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L-lysine potentiates aminoglycosides against <i>Acinetobacter baumannii</i> via regulation of proton motive force and antibiotics uptake.

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