Interaction of β-lactam antibiotics with the mitochondrial carnitine/acylcarnitine transporter

Pochini, Lorena; Galluccio, Michele; Scumaci, Domenica; Giangregorio, Nicola; Tonazzi, Annamaria; Palmieri, Ferdinando; Indiveri, Cesare

doi:10.1016/j.cbi.2008.03.003

Cited by 44 publications

(27 citation statements)

References 26 publications

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“…Although we present results on three major classes of bactericidal antibiotics, interrogation across a broader range of antibiotic classes is warranted before conclusions can be drawn about the general category of bactericidal antibiotics. Last, it has been shown that both bactericidal and bacteriostatic antibiotics target mitochondrial components (17–19, 23, 24), yet we observed a marked differential effect between bactericidal and bacteriostatic antibiotic treatments on cellular oxidative damage. Disentangling these differences in antibiotic action will be essential to gain a full understanding of how antibiotics interact with mammalian systems.…”

Section: Discussionmentioning

confidence: 52%

“…Indeed, previous studies in mammalian systems have revealed parallel antibiotic-target interactions in mitochondria (15–19, 32). It has been shown, for instance, that aminoglycosides target both bacterial (33) and mitochondrial ribosomes (16), quinolones target bacterial gyrases (34) and mtDNA topoisomerases (15), and β-lactams inhibit bacterial cell wall synthesis (35) and mitochondrial carnitine/acylcarnitine transporters (19). The work presented here advances our understanding of antibiotic action in mammalian systems in two distinct and important ways.…”

Section: Discussionmentioning

confidence: 99%

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Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells

et al. 2013

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Prolonged antibiotic treatment can lead to detrimental side effects in patients, including ototoxicity, nephrotoxicity, and tendinopathy, yet the mechanisms underlying the effects of antibiotics in mammalian systems remain unclear. It has been suggested that bactericidal antibiotics induce the formation of toxic reactive oxygen species (ROS) in bacteria. We show that clinically relevant doses of bactericidal antibiotics—quinolones, aminoglycosides, and β-lactams—cause mitochondrial dysfunction and ROS overproduction in mammalian cells. We demonstrate that these bactericidal antibiotic–induced effects lead to oxidative damage to DNA, proteins, and membrane lipids. Mice treated with bactericidal antibiotics exhibited elevated oxidative stress markers in the blood, oxidative tissue damage, and up-regulated expression of key genes involved in antioxidant defense mechanisms, which points to the potential physiological relevance of these antibiotic effects. The deleterious effects of bactericidal antibiotics were alleviated in cell culture and in mice by the administration of the antioxidant N-acetyl-L-cysteine or prevented by preferential use of bacteriostatic antibiotics. This work highlights the role of antibiotics in the production of oxidative tissue damage in mammalian cells and presents strategies to mitigate or prevent the resulting damage, with the goal of improving the safety of antibiotic treatment in people.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells

et al. 2013

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“…Quinolones are known to act on bacterial gyrases and mtDNA topoisomerases [168,169]. Similarly, β-lactams are found to inhibit cell wall synthesis in bacteria and carnitine/acylcarnitine transporters in mitochondria [170,171]. Thus, bactericidal antibiotics have proven to adversely affect the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Antibiotics-Induced Obesity: A Mitochondrial Perspective

Andrade

Jayaprakash

Bhat

et al. 2017

Public Health Genomics

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Antibiotics are the first line of treatment against infections and have contributed immensely to reduce the morbidity and mortality rates. Recently, extensive use of antibiotics has led to alterations of the gut microbiome, predisposition to various diseases and most importantly, increase in the emergence of antibiotic-resistant bacteria, which poses a major threat to global public health. Another major issue faced worldwide due to unregulated use of antibiotics in children as well as in adults is the influence of metabolism and body weight homeostasis, leading to obesity. Apart from the involvement of biosocial causes influencing diet, physical activity, and antibiotic use, pathogenesis of obesity is linked to interconnected functional alterations in cells, tissues and organs due to biochemical, epigenetic and genetic factors. Mitochondrial dysfunction is one such factor, which is becoming the primary focus of various aspects of research on multifactorial complex diseases and is providing new perspectives on etiology, biomarker-based diagnosis, and drug sensitivity. Through this review, we have made an attempt to present the interplay between use of antibiotics, obesity, and associated mitochondrial dysfunction. This may provide insights into the molecular basis, genetic predisposition and environmental triggers, which in turn may have potential clinical applications in the management of antibiotic use.

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“…Chronic antibiotic administration inhibits carnitine absorption and reabsorption by the intestines and kidney, respectively (Pochini et al, 2008). The limited circulating carnitine may eventually be depleted if bound for prolonged periods to unprocessed fatty acids, as would occur when mitochondrial fatty-acid beta oxidation is suppressed (Haas et al, 2008).…”

Section: Potential Mechanism Microbiota Alterations Lead To Asd and Rmentioning

confidence: 99%

Microbiome Disturbances and Autism Spectrum Disorders

2015

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Autism spectrum disorders (ASDs) are considered a heterogenous set of neurobehavioral diseases, with the rates of diagnosis dramatically increasing in the past few decades. As genetics alone does not explain the underlying cause in many cases, attention has turned to environmental factors as potential etiological agents. Gastrointestinal disorders are a common comorbidity in ASD patients. It was thus hypothesized that a gut-brain link may account for some autistic cases. With the characterization of the human microbiome, this concept has been expanded to include the microbiota-gut-brain axis. There are mounting reports in animal models and human epidemiologic studies linking disruptive alterations in the gut microbiota or dysbiosis and ASD symptomology. In this review, we will explore the current evidence that gut dysbiosis in animal models and ASD patients correlates with disease risk and severity. The studies to date have surveyed how gut microbiome changes may affect these neurobehavioral disorders. However, we harbor other microbiomes in the body that might impact brain function. We will consider microbial colonies residing in the oral cavity, vagina, and the most recently discovered one in the placenta. Based on the premise that gut microbiota alterations may be causative agents in ASD, several therapeutic options have been tested, such as diet modulations, prebiotics, probiotics, synbiotics, postbiotics, antibiotics, fecal transplantation, and activated charcoal. The potential benefits of these therapies will be considered. Finally, the possible mechanisms by which changes in the gut bacterial communities may result in ASD and related neurobehavioral disorders will be examined.

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Interaction of β-lactam antibiotics with the mitochondrial carnitine/acylcarnitine transporter

Cited by 44 publications

References 26 publications

Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells

Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells

Antibiotics-Induced Obesity: A Mitochondrial Perspective

Microbiome Disturbances and Autism Spectrum Disorders

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