Semisynthetic Analogues of Anhydrotetracycline as Inhibitors of Tetracycline Destructase Enzymes

Markley, Jana L.; Fang, Luting; Gasparrini, Andrew J.; Symister, Chanez T.; Kumar, Hirdesh; Tolia, Niraj H.; Dantas, Gautam; Wencewicz, Timothy A.

doi:10.1021/acsinfecdis.8b00349

Cited by 31 publications

(40 citation statements)

References 66 publications

(167 reference statements)

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“…Single amino-acid mutations in Tet(X) have been shown to provide gain-of-function under tigecycline selection through more efficient oxidative inactivation 22 . Thus, monitoring broadly for Tet(X) homologs, even single amino-acid point mutants, and understanding the evolutionary connection with the soil tetracycline-inactivating enzymes is critical for proactively managing this emerging resistance mechanism through optimization of next-generation tetracycline structures and the development of effective inhibitor combinations that overcome resistance by inactivation 23 .…”

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confidence: 99%

Tetracycline-inactivating enzymes from environmental, human commensal, and pathogenic bacteria cause broad-spectrum tetracycline resistance

Gasparrini¹,

et al. 2020

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Tetracycline resistance by antibiotic inactivation was first identified in commensal organisms but has since been reported in environmental and pathogenic microbes. Here, we identify and characterize an expanded pool of tet(X)-like genes in environmental and human commensal metagenomes via inactivation by antibiotic selection of metagenomic libraries. These genes formed two distinct clades according to habitat of origin, and resistance phenotypes were similarly correlated. Each gene isolated from the human gut encodes resistance to all tetracyclines tested, including eravacycline and omadacycline. We report a biochemical and structural characterization of one enzyme, Tet(X7). Further, we identify Tet(X7) in a clinical Pseudomonas aeruginosa isolate and demonstrate its contribution to tetracycline resistance. Lastly, we show anhydrotetracycline and semi-synthetic analogues inhibit Tet(X7) to prevent enzymatic tetracycline degradation and increase tetracycline efficacy against strains expressing tet(X7). This work improves our understanding of resistance by tetracyclineinactivation and provides the foundation for an inhibition-based strategy for countering resistance.

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confidence: 99%

Tetracycline-inactivating enzymes from environmental, human commensal, and pathogenic bacteria cause broad-spectrum tetracycline resistance

Gasparrini¹,

et al. 2020

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“…This powerful structure–function investigation led to the conclusion that anhydrotetracycline could be coupled with tetracyclines to inhibit this class of enzymes, which was validated in vitro and against model pathogens expressing tetracycline destructases . Recently these same authors described a novel synthesis scheme for generating semisynthetic anhydrotetracycline derivatives with broader inhibitor potency and enzyme specificity, including rescue of next‐generation tetracyclines against soil‐derived, pathogen‐derived, and human gut‐derived tetracycline destructases . This functional approach to ARG discovery provided a unique, proactive opportunity to discover new therapeutic compounds to counteract an emerging threat before it explodes into the wider population, which is particularly significant given the recent identification of Tet(X) in a number of multidrug‐resistant pathogens and the even more recent clinical approvals of next‐generation tetracycline antibiotics—eravacyline and omadacycline …”

Section: Functional Metagenomicsmentioning

confidence: 99%

“…90 Recently these same authors described a novel synthesis scheme for generating semisynthetic anhydrotetracycline derivatives with broader inhibitor potency and enzyme specificity, including rescue of next-generation tetracyclines against soil-derived, pathogen-derived, and human gut-derived tetracycline destructases. 92 This functional approach to ARG discovery provided a unique, proactive opportunity to discover new therapeutic compounds to counteract an emerging threat before it explodes into the wider population, which is particularly significant given the recent identification of Tet(X) in a number of multidrug-resistant pathogens 93 and the even more recent clinical approvals of next-generation tetracycline antibiotics-eravacyline and omadacycline. 94,95 Screening for hits in a functional metagenomic library is most convenient when the desired outcome is gain-of-function required for survival of the transformed host bacterium.…”

Section: Functional Metagenomicsmentioning

confidence: 99%

Genomic and Metagenomic Approaches for Predictive Surveillance of Emerging Pathogens and Antibiotic Resistance

Sukhum

Diorio-Toth

Dantas

2019

Clin Pharma and Therapeutics

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Antibiotic‐resistant organisms (AROs) are a major concern to public health worldwide. While antibiotics have been naturally produced by environmental bacteria for millions of years, modern widespread use of antibiotics has enriched resistance mechanisms in human‐impacted bacterial environments. Antibiotic resistance genes (ARGs) continue to emerge and spread rapidly. To combat the global threat of antibiotic resistance, researchers must develop methods to rapidly characterize AROs and ARGs, monitor their spread across space and time, and identify novel ARGs and resistance pathways. We review how high‐throughput sequencing‐based methods can be combined with classic culture‐based assays to characterize, monitor, and track AROs and ARGs. Then, we evaluate genomic and metagenomic methods for identifying ARGs and biosynthetic pathways for novel antibiotics from genomic data sets. Together, these genomic analyses can improve surveillance and prediction of emerging resistance threats and accelerate the development of new antibiotic therapies to combat resistance.

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“…(b)). Synthetic anhydrotetracycline analogues, for instance, are under consideration[95] as a pro-active inhibitor of enzymatic tetracycline degradation in E. coli expressing tetracycline destructase enzymes (Figure 5(a)).…”

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confidence: 99%

“…(a) In vitro inhibition by different synthetic anhydrotetracycline (aTC) analogues of tetracycline destructase degradation as a function of inhibitor concentration, measured using an optical absorbance kinetic assay and expressed as a velocity parameter[95]. (with permission from Springer).…”

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confidence: 99%

Circumventing antimicrobial-resistance and preventing its development in novel, bacterial infection-control strategies

Jiang

Gao

et al. 2020

Expert Opinion on Drug Delivery

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Introduction: Development of new antimicrobials with ever 'better' bacterial killing has long been considered the appropriate response to the growing threat of antimicrobial-resistant infections. However, the time-period between the introduction of a new antibiotic and the appearance of resistance amongst bacterial pathogens is getting shorter and shorter. This suggests that alternative pathways than making ever 'better' antimicrobials should be taken. Areas covered: This review aims to answer the questions (1) whether we have means to circumvent existing antibiotic-resistance mechanisms, (2) whether we can revert existing antibiotic-resistance, (3) how we can prevent the development of antimicrobial-resistance against novel infection-control strategies, including nano-antimicrobials. Expert opinion: Relying on relieving antibiotic-pressure and natural outcompeting of antimicrobialresistant bacteria seems an uncertain way out of the antibiotic-crisis facing us. Novel, non-antibiotic, nanotechnology-based infection control-strategies are promising. At the same time, rapid development of new resistance mechanisms once novel strategies is taken into global clinical use, may not be ruled out and must be closely monitored. This suggests focusing research and development on designing suitable combinations of existing antibiotics with new nano-antimicrobials in a way that induction of new antimicrobial-resistance mechanisms is avoided. The latter suggestion, however, requires a change of focus in research and development.

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Semisynthetic Analogues of Anhydrotetracycline as Inhibitors of Tetracycline Destructase Enzymes

Cited by 31 publications

References 66 publications

Tetracycline-inactivating enzymes from environmental, human commensal, and pathogenic bacteria cause broad-spectrum tetracycline resistance

Tetracycline-inactivating enzymes from environmental, human commensal, and pathogenic bacteria cause broad-spectrum tetracycline resistance

Genomic and Metagenomic Approaches for Predictive Surveillance of Emerging Pathogens and Antibiotic Resistance

Circumventing antimicrobial-resistance and preventing its development in novel, bacterial infection-control strategies

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