Nalidixic Acid-Resistant Mutants of
            <i>Escherichia coli</i>
            Deficient in Isocitrate Dehydrogenase

Helling, Robert B.; Kukora, John S.

doi:10.1128/jb.105.3.1224-1226.1971

Cited by 41 publications

(28 citation statements)

References 14 publications

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“…Because the activity of these metabolic networks is relevant for the activity of the antibiotics, alterations in bacterial metabolism should influence the susceptibility to these antimicrobials. In agreement with this statement, it has been described that E. coli mutants lacking isocitrate dehydrogenase (Helling & Kukora, 1971) or aconitase B are resistant to quinolones (Gruer et al, 1997).…”

Section: Intrinsic Resistancementioning

confidence: 53%

Metabolic regulation of antibiotic resistance

2011

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It is generally assumed that antibiotics and resistance determinants are the task forces of a biological warfare in which each resistance determinant counteracts the activity of a specific antibiotic. According to this view, antibiotic resistance might be considered as a specific response to an injury, not necessarily linked to bacterial metabolism, except for the burden that the acquisition of resistance might impose on the bacteria (fitness costs). Nevertheless, it is known that changes in bacterial metabolism, such as those associated with dormancy or biofilm formation, modulate bacterial susceptibility to antibiotics (phenotypic resistance), indicating that there exists a linkage between bacterial metabolism and antibiotic resistance. The analyses of the intrinsic resistomes of bacterial pathogens also demonstrate that the building up of intrinsic resistance requires the concerted action of many elements, several of which play a relevant role in the bacterial metabolism. In this article, we will review the current knowledge on the linkage between bacterial metabolism and antibiotic resistance and will discuss the role of global metabolic regulators such as Crc in bacterial susceptibility to antibiotics. Given that growing into the human host requires a metabolic adaptation, we will discuss whether this adaptation might trigger resistance even in the absence of selective pressure by antibiotics.

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Section: Intrinsic Resistancementioning

confidence: 53%

Metabolic regulation of antibiotic resistance

2011

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“…Another mutant had an SNP mutation in the proline transport gene proV , which occurred in a multi-drug-resistant Salmonella strain (45). The third mutant had an SNP mutation in an isocitrate dehydrogenase encoding gene icd , the mutation of which has been observed in E. coli mutants resistant to nalidixic acid (46). Together, many of the identified mutated genes in the Amp-resistant strains isolated from both co-exposure and Amp-exposure conditions have resistance-related functions, which likely led to the development of Amp-resistance.…”

Section: Resultsmentioning

confidence: 99%

Exposure to environmental level pesticides stimulates and diversifies evolution inEscherichia colitowards greater antibiotic resistance

Xing

Men

2019

Preprint

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1Antibiotic resistance is one of the most challenging issues in public health. Antibiotic resistance 2 can be selected by antibiotics at sub-inhibitory concentrations, the concentrations typically 3 occurring in natural and engineered environments. Meanwhile, many other emerging organic 4 contaminants such as pesticides are frequently co-occurring with antibiotics in agriculture-related 5 environments and municipal wastewater treatment plants. To investigate the effects of the co-6 existing, non-antibiotic pesticides on the development of antibiotic resistance, we conducted 7 long-term exposure experiments using a model Escherichia coli strain. The results revealed that 8 1) the exposure to a high level (in mg/L) of pesticides alone led to the emergence of mutants with 9 significantly higher resistance to streptomycin; 2) the exposure to an environmental level (in 10 µg/L) of pesticides together with a sub-inhibitory level (in sub mg/L) of ampicillin 11 synergistically stimulated the selection of ampicillin resistance and the cross-selection of 12 resistance to three other antibiotics (i.e., ciprofloxacin, chloramphenicol, and tetracycline). 13 Resistance levels of mutants selected from co-exposure were significantly higher than those of 14 mutants selected from ampicillin exposure only. The comparative genomic and transcriptomic 15 analyses indicate that distinct and diversified genetic mutations in ampicillin-and ciprofloxacin-16 resistant mutants were selected from co-exposure, which likely caused holistic transcriptional 17 regulation and the increased antibiotic resistance. Together, the findings provide valuable 18 fundamental insights into the development of antibiotic resistance under environmentally 19 relevant conditions, as well as the underlying molecular mechanisms of the elevated antibiotic 20 resistance induced by the exposure to pesticides. 21 Escherichia coli 23 3 Significance statement 24 Antibiotic resistance is a major threat to public health globally. Besides clinically relevant 25 environments, the emergence and spread of resistant bacteria in non-clinical environments can 26 also potentially pose risks of therapy failures. This study showed that the long-term, 27 environment-level exposure to pesticides with and without antibiotics significantly stimulated the 28 development of greater antibiotic resistance. The resistant strains selected from the exposure to 29 pesticides are genetically and metabolically distinct from the ones selected by the antibiotic only. 30 Although it is still being debated regarding whether or not a large use of antibiotics in plant 31 agriculture is harmful, our findings provide the first fundamental evidence that greater concerns 32 of antibiotic resistance may result if antibiotics are applied together with non-antibiotic 33 pesticides. 34 35Antibiotic resistance has been one of the most challenging environmental and public health 36 issues. The de novo mutation is one important route for bacteria to acquire antibiotic resistance, 37 under both clinical an...

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“…Previous analysis has shown that E. coli mutants deficient in the metabolic enzyme isocitrate dehydrogenase are resistant to nalidixic acid (35). However, little work is still available in the crosstalk between metabolism (and metabolic robustness) and antibiotic resistance (57, 58), despite the fact that metabolic interventions may improve the activity of the antibiotics (33, 59-61) and that bacterial metabolism can constrain the evolution of antibiotic resistance (13).…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that antibiotic resistance can be inter-linked to bacterial metabolism (33, 34). However, with very few exceptions (35), the mutational inactivation of genes encoding enzymes of the central carbon metabolism has not been considered to be a significant cause of antibiotic resistance in bacterial pathogens (34, 35). Our article hence shed light in the crosstalk between antibiotic resistance and central carbon metabolism in S. maltophilia .…”

Section: Introductionmentioning

confidence: 99%

The inactivation of enzymes belonging to the central carbon metabolism, a novel mechanism of developing antibiotic resistance

Gil-Gil

Corona

Martínez

et al. 2019

Preprint

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Fosfomycin is a bactericidal antibiotic, analogous to phosphoenolpyruvate (PEP) that exerts its activity by inhibiting the activity of MurA. This enzyme catalyzes the first step of peptidoglycan biosynthesis, the transfer of enolpyruvate from PEP to uridine-diphosphate-N-acetylglucosamine. Fosfomycin is increasingly used in the last years, mainly for treating infections caused by Gram-negative multidrug resistant bacteria as Stenotrophomonas maltophilia, an opportunistic pathogen characterized by its low susceptibility to antibiotics of common use. The mechanisms of mutational resistance to fosfomycin in S. maltophilia were studied in the current work. None of the mechanisms so far described for other organisms, which include the production of fosfomycin inactivating enzymes, target modification, induction of alternative peptidoglycan biosynthesis pathway and the impaired entrance of the antibiotic, are involved in the acquisition of such resistance by this bacterial species. Rather the unique cause of resistance in the studied mutants is the mutational inactivation of different enzymes belonging to the Embden-Meyerhof-Parnas central metabolism pathway. The amount of intracellular fosfomycin accumulation did not change in any of these mutants showing that neither the inactivation nor the transport of the antibiotic were involved. Transcriptomic analysis also showed that the mutants did not present changes in the expression level of putative alternative peptidoglycan biosynthesis pathway genes neither any related enzyme. Finally, the mutants did not present an increased PEP concentration that might compete with fosfomycin for its binding to MurA. Based on these results, we describe a completely novel mechanism of antibiotic resistance based on the remodeling of S. maltophilia metabolism.SignificanceAntibiotic resistance (AR) has been largely considered as a specific bacterial response to an antibiotic challenge. Indeed, its study has been mainly concentrated in mechanisms that affect the antibiotics (mutations in transporters, the activity of efflux pumps and antibiotic modifying enzymes) or their targets (i.e.: target mutations, protection or bypass). Usually, AR-associated metabolic changes were considered to be a consequence (fitness costs) and not a cause of AR. Herein, we show that strong alterations in the bacterial metabolism can also be the cause of AR. In the study here presented, Stenotrophomonas maltophilia acquires fosfomycin resistance through the inactivation of glycolytic enzymes belonging to the Embden-Meyerhof-Parnas. Besides resistance to fosfomycin, this inactivation also impairs the bacterial gluconeogenic pathway. Together with previous work showing that AR can be under metabolic control, our results provide evidence that AR is intertwined with the bacterial metabolism.

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Nalidixic Acid-Resistant Mutants of Escherichia coli Deficient in Isocitrate Dehydrogenase

Abstract: icd Mutants of Escherichia coli K-12, selected for their resistance to nalidixic acid, are deficient in isocitrate dehydrogenase.

Cited by 41 publications

References 14 publications

Metabolic regulation of antibiotic resistance

Metabolic regulation of antibiotic resistance

Exposure to environmental level pesticides stimulates and diversifies evolution inEscherichia colitowards greater antibiotic resistance

The inactivation of enzymes belonging to the central carbon metabolism, a novel mechanism of developing antibiotic resistance

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