Chemical decay of an antibiotic inverts selection for resistance

Palmer, Adam C.; Angelino, Elaine; Kishony, Roy

doi:10.1038/nchembio.289

Cited by 74 publications

(57 citation statements)

References 24 publications

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“…Previously, we observed that anhydrotetracycline, a key biosynthetic precursor 41 and degradation product 42 of tetracycline with poor antibiotic activity was not degraded by Tet(47-56) 28 . None the less, it is known to be an effector of tetracycline producers and tetracycline-resistant bacteria by inducing expression of energetically expensive tetracycline efflux pumps, permitting tetracycline producers to survive and selecting against tetracycline resistance 43 . Based on the structural similarity to tetracycline and the intimate role that anhydrotetracycline plays in tetracycline biology, we hypothesized that anhydrotetracycline represents an evolutionarily-privileged chemical lead for inhibitor design.…”

Section: Resultsmentioning

confidence: 99%

Plasticity, dynamics, and inhibition of emerging tetracycline resistance enzymes

et al. 2017

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While tetracyclines are an important class of antibiotics in agriculture and the clinic, their efficacy is threatened by increasing resistance. Resistance to tetracyclines can occur through efflux, ribosomal protection, or enzymatic inactivation. Surprisingly, tetracycline enzymatic inactivation has remained largely unexplored despite providing the distinct advantage of antibiotic clearance. The tetracycline destructases are a recently-discovered family of tetracycline-inactivating flavoenzymes from pathogens and soil metagenomes with a high potential for broad dissemination. Here, we show tetracycline destructases accommodate tetracycline-class antibiotics in diverse and novel orientations for catalysis, and antibiotic binding drives unprecedented structural dynamics facilitating tetracycline inactivation. We identify a key inhibitor binding mode that locks the flavin adenine dinucleotide cofactor in an inactive state, functionally rescuing tetracycline activity. Our results reveal the potential of a novel tetracycline/tetracycline destructase inhibitor combination therapy strategy to overcome resistance by enzymatic inactivation and restore the use of an important class of antibiotics.

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Section: Resultsmentioning

confidence: 99%

Plasticity, dynamics, and inhibition of emerging tetracycline resistance enzymes

et al. 2017

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“…Transfer of this self-immunity pump to nonproducer organisms enables them to resist tetracycline [32]. Interestingly, the natural decay of tetracycline to anhydrotetracycline can invert the selective advantage of cohabiting resistant strains over susceptible ones, because of the fitness cost of constitutive TetA expression in the resistant strains through anhydrotetracycline induction [33]. This highlights the complex ecological interplay between antibiotic production, degradation, and resistance.…”

Section: Repurposing Environmental Genes: the 'Original' Resistomementioning

confidence: 97%

Context matters — the complex interplay between resistome genotypes and resistance phenotypes

Dantas

Sommer

2012

Current Opinion in Microbiology

109

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“…In this study, transformed E. coli exhibited enhanced susceptibility to aloin than non-transformed E. coli. The increased susceptibility could be explained by 'negative cross-resistance' or 'collateral sensitivity', where the induction of resistance to one compound enhances the toxicity to other compounds (Li et al 2002;Palmer et al 2010). Previously, similar phenomenon was observed through the increased susceptibility of E. coli to fusaric acid consequent to development of resistance against tetracyclines by modification of efflux pumps (Bochner et al 1980).…”

Section: Minimum Inhibitory Concentrationmentioning

confidence: 82%

First report on rapid screening of nanomaterial-based antimicrobial agents against β-lactamase resistance using pGLO plasmid transformed Escherichia coli HB 101 K-12

Raj¹,

Yegireddy²,

Sravanthi³

et al. 2015

Appl Nanosci

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Combating antibiotic resistance requires discovery of novel antimicrobials effective against resistant bacteria. Herein, we present for the first time, pGLO plasmid transformed Escherichia coli HB 101 K 12 as novel model for screening of nanomaterial-based antimicrobial agents against b-lactamase resistance. E. coli HB 101 was transformed by pGLO plasmid in the presence of calcium chloride (50 mM; pH 6.1) aided by heat shock (0-42-0°C). The transformed bacteria were grown on Luria-Bertani agar containing ampicillin (amp) and arabinose (ara). The transformed culture was able to grow in the presence of ampicillin and also exhibited fluorescence under UV light. Both untransformed and transformed bacteria were used for screening citrate-mediated nanosilver (CNS), aloin-mediated nanosilver (ANS), 11-a-ketoboswellic acid (AKBA)-mediated nanosilver (BNS); nanozinc oxide, nanomanganese oxide (NMO) and phytochemicals such as aloin and AKBA. Minimum inhibitory concentrations (MIC) were obtained by microplate method using q-iodo nitro tetrazolium indicator. All the compounds were effective against transformed bacteria except NMO and AKBA. Transformed bacteria exhibited reverse cross resistance against aloin. ANS showed the highest antibacterial activity with a MIC of 0.32 ppm followed by BNS (10.32 ppm), CNS (20.64 ppm) and NZO (34.83 ppm). Thus, pGLO plasmid can be used to induce resistance against b-lactam antibiotics and the model can be used for rapid screening of new antibacterial agents effective against resistant bacteria.

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Chemical decay of an antibiotic inverts selection for resistance

Cited by 74 publications

References 24 publications

Plasticity, dynamics, and inhibition of emerging tetracycline resistance enzymes

Plasticity, dynamics, and inhibition of emerging tetracycline resistance enzymes

Context matters — the complex interplay between resistome genotypes and resistance phenotypes

First report on rapid screening of nanomaterial-based antimicrobial agents against β-lactamase resistance using pGLO plasmid transformed Escherichia coli HB 101 K-12

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