Elucidation of Mycobacterium abscessus aminoglycoside and capreomycin resistance by targeted deletion of three putative resistance genes

Rominski, Anna; Selchow, Petra; Becker, Katja; Brülle, Juliane K.; Molin, Michael Dal; Sander, Peter

doi:10.1093/jac/dkx125

Cited by 57 publications

(95 citation statements)

References 39 publications

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“…The potency of amikacin is dampened by M. abscessus expression of Eis2, an enzyme that modifies aminoglycosides [16]. It is possible that rifamycin-mediated transcription inhibition also enhances the potency of amikacin by reducing induction of Eis2.…”

Section: Partners In Crime: Harnessing Antibacterial Drug Synergiesmentioning

confidence: 99%

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Repositioning rifamycins for Mycobacterium abscessus lung disease

Ganapathy

Dartois

Dick

2019

Expert Opinion on Drug Discovery

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Introduction: The treatment of Mycobacterium abscessus lung disease faces significant challenges due to intrinsic antibiotic resistance. New drugs are needed to cure this incurable disease. The key anti-tubercular rifamycin, rifampicin, suffers from low potency against M. abscessus and is not used clinically. Recently, another member of the rifamycin class, rifabutin, was shown to be active against the opportunistic pathogen. Areas covered: In this review, the authors discuss the rifamycins as a reemerging drug class for treating M. abscessus infections. The authors focus on the differential potency of rifampicin and rifabutin against M. abscessus in the context of intrinsic antibiotic resistance and bacterial uptake and metabolism. Reports of rifamycin-based drug synergies and rifamycin potentiation by host-directed therapy are evaluated. Expert opinion: While repurposing rifabutin for M. abscessus lung disease may provide some immediate relief, the repositioning (chemical optimization) of rifamycins offers long-term potential for improving clinical outcomes. Repositioning will require a multifaceted approach involving renewed screening of rifamycin libraries, medicinal chemistry to improve 'bacterial cell pharmacokinetics', better models of bacterial pathophysiology and infection, and harnessing of drug synergies and host-directed therapy towards the development of a better drug regimen. ARTICLE HISTORY

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Section: Partners In Crime: Harnessing Antibacterial Drug Synergiesmentioning

confidence: 99%

“…All NTM species and particularly M. abscessus are intrinsically resistant to many drug classes [9][10][11][12]. Among the many factors underlying M. abscessus' natural drug resistance, the pathogen's ability to metabolize most antibiotic classes and convert them to inactive derivatives stands as a key mechanism [10,[13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Repositioning rifamycins for Mycobacterium abscessus lung disease

Ganapathy

Dartois

Dick

2019

Expert Opinion on Drug Discovery

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“…In summary, we report here the high-resolution xray structure of Mabs_Eis2, previously shown to participate in resistance to AG resistance in Mabs [18,30]. Of clinical importance, this work demonstrates that Mabs_Eis2 is involved in the direct modification of AMK, one of the most commonly used antibiotics for the treatment of Mabs infections [36].…”

Section: Aminoglycosides Recognition and Catalytic Efficienciesmentioning

confidence: 78%

“…In contrast, Mabs_Eis2, similar to its M.tb homolog, exhibits a broad specificity for AG substrates and can use acetyl-CoA (ACO) as a cofactor and acetyl group donor. Consistently, a Mabs_eis2 deletion mutant was more susceptible to AG, such as hygromycin B (HYG) and another antibiotic class notably capreomycin than the wild-type strain [18,28]. In addition, this mutant showed also a reduced capacity of survival in macrophages as compared to its parental or complemented counterparts [29].…”

Section: Introductionmentioning

confidence: 83%

Crystal structure of the aminoglycosides N‐acetyltransferase Eis2 from Mycobacterium abscessus

et al. 2019

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Mycobacterium abscessus is an emerging human pathogen that is notorious for being one of the most drug‐resistant species of Mycobacterium. It has developed numerous strategies to overcome the antibiotic stress response, limiting treatment options and leading to frequent therapeutic failure. The panel of aminoglycosides (AG) usually used in the treatment of M. abscessus pulmonary infections is restricted by chemical modification of the drugs by the N‐acetyltransferase Eis2 protein (Mabs_Eis2). This enzyme acetylates the primary amine of AGs, preventing these antibiotics from binding ribosomal RNA and thereby impairing their activity. In this study, the high‐resolution crystal structures of Mabs_Eis2 in its apo‐ and cofactor‐bound forms were solved. The structural analysis of Mabs_Eis2, supported by the kinetic characterization of the enzyme, highlights the large substrate specificity of the enzyme. Furthermore, in silico docking and biochemical approaches attest that Mabs_Eis2 modifies clinically relevant drugs such as kanamycin and amikacin, with a better efficacy for the latter. In line with previous biochemical and in vivo studies, our work suggests that Mabs_Eis2 represents an attractive pharmacological target to be further explored. The high‐resolution crystal structures presented here may pave the way to the design of Eis2‐specific inhibitors with the potential to counteract the intrinsic resistance levels of M. abscessus to an important class of clinically important antibiotics. Database Structural data are available in the PDB database under the accession numbers: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6RFY, http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6RFX and http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6RFT.

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“…Infection clearance after up to 3 years of antibiotic treatment is achieved in only 10-55% of patients (8). This level of treatment failure is likely partly due to intrinsic antibiotic resistance (9-11); however, antibiotic tolerance may also play a role (12), though the environmental conditions that may induce tolerance in this organism are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Biofilm-associatedMycobacterium abscessuscells have altered antibiotic tolerance and surface glycolipids in Artificial Cystic Fibrosis Sputum Media

Hunt-Serracin

Parks

Boll

et al. 2018

Preprint

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8Mycobacterium abscessus (Mab) is a biofilm-forming, multi-drug resistant, non-9 tuberculous mycobacterial (NTM) pathogen increasingly found in Cystic Fibrosis 10 patients. Antibiotic treatment for these infections is often unsuccessful, partly due to 11 Mab's high intrinsic antibiotic resistance. It is not clear whether antibiotic tolerance 12 caused by biofilm formation also contributes to poor treatment outcomes. We studied 13 the surface glycolipids and antibiotic tolerance of Mab biofilms grown in Artificial Cystic 14 Fibrosis Sputum (ACFS) media in order to determine how they are affected 15 by nutrient conditions that mimic infection. We found that Mab displays more of the 16 virulence lipid trehalose dimycolate when grown in ACFS compared to standard lab 17 media. In ACFS media, biofilm-associated cells are more antibiotic tolerant than 18 planktonic cells in the same well. This contrasts with standard lab medias, where biofilm 19 and planktonic cells are both highly antibiotic tolerant. These results indicate that Mab 20 cell physiology in biofilms depends on environmental factors, and that nutrient 21 conditions found within Cystic Fibrosis infections could contribute to both increased 22 virulence and antibiotic tolerance.23 Concentration(μg/mL) Concentration(μg/mL) Concentration(μg/mL) Concentration(μg/mL) Concentration(μg/mL) Concentration(μg/mL) Concentration(μg/mL) Concentration(μg/mL) Amikacin Cefoxitin Clarithromycin Amikacin Cefoxitin Clarithromycin

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Elucidation of Mycobacterium abscessus aminoglycoside and capreomycin resistance by targeted deletion of three putative resistance genes

Abstract: M. abscessus expresses two distinct AG resistance determinants, AAC(2 ' ) and Eis2, which confer clinically relevant drug resistance.

Cited by 57 publications

References 39 publications

Repositioning rifamycins for Mycobacterium abscessus lung disease

Repositioning rifamycins for Mycobacterium abscessus lung disease

Crystal structure of the aminoglycosides N‐acetyltransferase Eis2 from Mycobacterium abscessus

Biofilm-associatedMycobacterium abscessuscells have altered antibiotic tolerance and surface glycolipids in Artificial Cystic Fibrosis Sputum Media

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