Potent 1,2,4-Triazino[5,6<i>b</i>]indole-3-thioether Inhibitors of the Kanamycin Resistance Enzyme Eis from <i>Mycobacterium tuberculosis</i>

Ngo, Huy; Green, Keith D.; Gajadeera, Chathurada S.; Willby, Melisa J.; Holbrook, Selina Y. L.; Hou, Can; Garzan, Atefeh; Mayhoub, Abdelrahman S.; Posey, James E.; Tsodikov, Oleg V.

doi:10.1021/acsinfecdis.8b00074

Cited by 22 publications

(33 citation statements)

References 23 publications

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“…Recently, several structurally diverse competitive Eis inhibitors with 1,2,4-triazino[5,6 b ]indole-3-thioether-based, sulfonamide-based, pyrrolo[1,5- a ]pyrazine-based and isothiazole S,S -dioxide heterocyclic scaffolds were identified by high-throughput screenings of large compound libraries. Importantly, few promising inhibitors could completely restore kanamycin susceptibility in a kanamycin resistant M. tuberculosis strain in vitro at concentrations that were non-cytotoxic to mammalian cells ( Green et al, 2012 ; Garzan et al, 2016 , 2017 ; Willby et al, 2016 ; Ngo et al, 2018 ). Remarkably, inhibitors designed for M. tuberculosis Eis, were also found to be active against Eis homologs in M. smegmatis and A. variabilis ( Chen et al, 2012 ; Pricer et al, 2012 ).…”

Section: Clinical Relevancementioning

confidence: 99%

The Role of Antibiotic-Target-Modifying and Antibiotic-Modifying Enzymes in Mycobacterium abscessus Drug Resistance

2018

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The incidence and prevalence of non-tuberculous mycobacterial (NTM) infections have been increasing worldwide and lately led to an emerging public health problem. Among rapidly growing NTM, Mycobacterium abscessus is the most pathogenic and drug resistant opportunistic germ, responsible for disease manifestations ranging from “curable” skin infections to only “manageable” pulmonary disease. Challenges in M. abscessus treatment stem from the bacteria’s high-level innate resistance and comprise long, costly and non-standardized administration of antimicrobial agents, poor treatment outcomes often related to adverse effects and drug toxicities, and high relapse rates. Drug resistance in M. abscessus is conferred by an assortment of mechanisms. Clinically acquired drug resistance is normally conferred by mutations in the target genes. Intrinsic resistance is attributed to low permeability of M. abscessus cell envelope as well as to (multi)drug export systems. However, expression of numerous enzymes by M. abscessus, which can modify either the drug-target or the drug itself, is the key factor for the pathogen’s phenomenal resistance to most classes of antibiotics used for treatment of other moderate to severe infectious diseases, like macrolides, aminoglycosides, rifamycins, β-lactams and tetracyclines. In 2009, when M. abscessus genome sequence became available, several research groups worldwide started studying M. abscessus antibiotic resistance mechanisms. At first, lack of tools for M. abscessus genetic manipulation severely delayed research endeavors. Nevertheless, the last 5 years, significant progress has been made towards the development of conditional expression and homologous recombination systems for M. abscessus. As a result of recent research efforts, an erythromycin ribosome methyltransferase, two aminoglycoside acetyltransferases, an aminoglycoside phosphotransferase, a rifamycin ADP-ribosyltransferase, a β-lactamase and a monooxygenase were identified to frame the complex and multifaceted intrinsic resistome of M. abscessus, which clearly contributes to complications in treatment of this highly resistant pathogen. Better knowledge of the underlying mechanisms of drug resistance in M. abscessus could improve selection of more effective chemotherapeutic regimen and promote development of novel antimicrobials which can overwhelm the existing resistance mechanisms. This article reviews the currently elucidated molecular mechanisms of antibiotic resistance in M. abscessus, with a focus on its drug-target-modifying and drug-modifying enzymes.

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Section: Clinical Relevancementioning

confidence: 99%

The Role of Antibiotic-Target-Modifying and Antibiotic-Modifying Enzymes in Mycobacterium abscessus Drug Resistance

2018

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“…Cross-resistance between kanamycin (KAN), amikacin (AMK) and capreomycin (CAP) is thought to be associated with mutations in the16S rRNA gene rrs , specifically at position A1401G (Alangaden et al, 1998; Oudghiri et al, 2018). Mutations in promoter region of eis gene, encoding an aminoglycoside acetyltransferase, caused low-level KAN resistance (Bauskenieks et al, 2015; Ngo et al, 2018). CAP resistance has been correlated with mutations in tlyA gene, which encodes a putative 2′- O -methyltransferase (TlyA) (Freihofer et al, 2016; Witek et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Mutation and Transmission Profiles of Second-Line Drug Resistance in Clinical Isolates of Drug-Resistant Mycobacterium tuberculosis From Hebei Province, China

Gao

Zhang

et al. 2019

Front. Microbiol.

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The emergence of drug-resistant tuberculosis (TB) is involved in ineffective treatment of TB, especially multidrug resistant/extensively resistant TB (MDR/XDR-TB), leading to acquired resistance and transmission of drug-resistant strains. Second-line drugs (SLD), including both fluoroquinolones and injectable drugs, were commonly proved to be the effective drugs for treatment of drug-resistant TB. The purpose of this study was to investigate the prevalence of SLD-resistant strains and its specific mutations in drug-resistant Mycobacterium tuberculosis clinical isolates, and to acknowledge the transmission pattern of SLD resistance strains in Hebei. The genes gyrA , gyrB , rrs , eis promoter and tlyA of 257 drug-resistant clinical isolates were sequenced to identify mutations that could be responsible for resistance against fluoroquinolones and second-line injectable drugs. Each isolate was genotyped by Spoligotyping and 15-loci MIRU-VNTR. Our results indicated that 48.2% isolates were resistant to at least one of five SLD. Of them, 37.7% isolates were resistant to fluoroquinolones and 24.5% isolates were resistant to second-line injectable drugs. Mutations in genes gyrA , gyrB , rrs , eis promoter and tlyA were detected in 73 (75.3%), 7 (7.2%), 24 (38.1%), 5 (7.9%), and 3 (4.8%) isolates, respectively. The most prevalent mutations were the D94G (23.7%) in gyrA gene and the A1401G (33.3%) in rrs gene. A combination of gyrA , rrs and eis promoter can act as a valuable predicator for predicting XDR phenotype. These results highlight the development of rapid diagnosis are the effective manners for the control of SLD-TB or XDR-TB.

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“…A second screening of a larger collection of small-molecule compounds resulted in the identification of several families of compounds capable of inhibiting Eis activity. These contained diverse chemical scaffolds (Garzan et al, 2016a,b, 2017; Willby et al, 2016; Ngo et al, 2018). Besides, these inhibitors were highly selective for Eis, and did not inhibited AACs from other families (Garzan et al, 2016b).…”

Section: The Eis Protein Becomes a Novel Aminoglycoside Acetyltransfementioning

confidence: 99%

“…Besides, these inhibitors were highly selective for Eis, and did not inhibited AACs from other families (Garzan et al, 2016b). More importantly, as these inhibitors bound in the AG pocket of the Eis protein, they were able to reverse kanamycin resistance of a M. tuberculosis isolate (Garzan et al, 2016b; Willby et al, 2016; Ngo et al, 2018). Some of these inhibitors, such as those based on a pyrrolo[1,5-a]pyrazine scaffold, also lacked any toxicity on mammalian cell lines (Garzan et al, 2017).…”

Section: The Eis Protein Becomes a Novel Aminoglycoside Acetyltransfementioning

confidence: 99%

Mycobacterial Aminoglycoside Acetyltransferases: A Little of Drug Resistance, and a Lot of Other Roles

et al. 2019

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Aminoglycoside acetyltransferases are important determinants of resistance to aminoglycoside antibiotics in most bacterial genera. In mycobacteria, however, aminoglycoside acetyltransferases contribute only partially to aminoglycoside susceptibility since they are related with low level resistance to these antibiotics (while high level aminoglycoside resistance is due to mutations in the ribosome). Instead, aminoglycoside acetyltransferases contribute to other bacterial functions, and this can explain its widespread presence along species of genus Mycobacterium. This review is focused on two mycobacterial aminoglycoside acetyltransferase enzymes. First, the aminoglycoside 2′-N-acetyltransferase [AAC(2′)], which was identified as a determinant of weak aminoglycoside resistance in M. fortuitum, and later found to be widespread in most mycobacterial species; AAC(2′) enzymes have been associated with resistance to cell wall degradative enzymes, and bactericidal mode of action of aminoglycosides. Second, the Eis aminoglycoside acetyltransferase, which was identified originally as a virulence determinant in M. tuberculosis (enhanced intracellular survival); Eis protein in fact controls production of pro-inflammatory cytokines and other pathways. The relation of Eis with aminoglycoside susceptibility was found after the years, and reaches clinical significance only in M. tuberculosis isolates resistant to the second-line drug kanamycin. Given the role of AAC(2′) and Eis proteins in mycobacterial biology, inhibitory molecules have been identified, more abundantly in case of Eis. In conclusion, AAC(2′) and Eis have evolved from a marginal role as potential drug resistance mechanisms into a promising future as drug targets.

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Potent 1,2,4-Triazino[5,6b]indole-3-thioether Inhibitors of the Kanamycin Resistance Enzyme Eis from Mycobacterium tuberculosis

Cited by 22 publications

References 23 publications

The Role of Antibiotic-Target-Modifying and Antibiotic-Modifying Enzymes in Mycobacterium abscessus Drug Resistance

The Role of Antibiotic-Target-Modifying and Antibiotic-Modifying Enzymes in Mycobacterium abscessus Drug Resistance

Mutation and Transmission Profiles of Second-Line Drug Resistance in Clinical Isolates of Drug-Resistant Mycobacterium tuberculosis From Hebei Province, China

Mycobacterial Aminoglycoside Acetyltransferases: A Little of Drug Resistance, and a Lot of Other Roles

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