Aminoglycoside-modifying enzymes determine the innate susceptibility to aminoglycoside antibiotics in rapidly growing mycobacteria

Maurer, Florian P.; Bruderer, Vera; Castelberg, Claudio; Ritter, Claudia; Shcherbakov, Dimitri; Bloemberg, Guido V.; Böttger, Erik C.

doi:10.1093/jac/dku550

Cited by 22 publications

(22 citation statements)

References 48 publications

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“…Although more than half of the M. abscessus isolates are moderately susceptible to moxifloxacin in some studies 66 67 , the results are controversial 68 . Moreover, regarding the bactericidal effects of amikacin and moxifloxacin against M. abscessus , none of these drugs showed bactericidal activity 69 70 71 . Considering drug toxicity and inconvenience, aggressive parenteral therapy was suggested for 2–4 months, followed by macrolide therapy with additional oral agents such as a fluoroquinolone, linezolid, clofazimine, or inhaled amikacin as a step-down therapy 65 .…”

Section: Treatment Of Ntm Lung Diseasementioning

confidence: 99%

Diagnosis and Treatment of Nontuberculous Mycobacterial Lung Disease: Clinicians' Perspectives

2016

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Nontuberculous mycobacteria (NTM) are emerging pathogens that affect both immunocompromised and immunocompetent patients. The incidence and prevalence of NTM lung disease are increasing worldwide and rapidly becoming a major public health problem. For the diagnosis of NTM lung disease, patients suspected to have NTM lung disease are required to meet all clinical and microbiologic criteria. The development of molecular methods allows the characterization of new species and NTM identification at a subspecies level. Even after the identification of NTM species from respiratory specimens, clinicians should consider the clinical significance of such findings. Besides the limited options, treatment is lengthy and varies by species, and therefore a challenge. Treatment may be complicated by potential toxicity with discouraging outcomes. The decision to start treatment for NTM lung disease is not easy and requires careful individualized analysis of risks and benefits. Clinicians should be alert to those unique aspects of NTM lung disease concerning diagnosis with advanced molecular methods and treatment with limited options. Current recommendations and recent advances for diagnosis and treatment of NTM lung disease are summarized in this article.

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Section: Treatment Of Ntm Lung Diseasementioning

confidence: 99%

Diagnosis and Treatment of Nontuberculous Mycobacterial Lung Disease: Clinicians' Perspectives

2016

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“…121, 133 Also, there is good evidence that another pathogenic mycobacteria, M. abscessus , contains a native AAC(2′) responsible for its intrinsic resistance to AGs. 134, 135 …”

Section: Ag-modifying Enzymesmentioning

confidence: 99%

Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives

2016

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Aminoglycoside (AG) antibiotics are used to treat many Gram-negative and some Gram-positive infections and, importantly, multidrug-resistant tuberculosis. Among various bacterial species, resistance to AGs arises through a variety of intrinsic and acquired mechanisms. The bacterial cell wall serves as a natural barrier for small molecules such as AGs and may be further fortified via acquired mutations. Efflux pumps work to expel AGs from bacterial cells, and modifications here too may cause further resistance to AGs. Mutations in the ribosomal target of AGs, while rare, also contribute to resistance. Of growing clinical prominence is resistance caused by ribosome methyltransferases. By far the most widespread mechanism of resistance to AGs is the inactivation of these antibiotics by AG-modifying enzymes. We provide here an overview of these mechanisms by which bacteria become resistant to AGs and discuss their prevalence and potential for clinical relevance.

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“…A worrying discovery that the genome of emerging pathogen M. abscessus encodes several putative aminoglycoside-modifying enzymes which include members of all three classes, came in 2009 when Ripoll et al first sequenced the complete genome of M. abscessus ( Ripoll et al, 2009 ). Some predictions were later substantiated by drug susceptibility testing and biochemical analysis ( Maurer et al, 2015 ). More recently, direct genetic evidence for a functional role of some of these putative aminoglycoside-modifying enzymes in M. abscessus intrinsic resistance to this antibiotic class, was obtained.…”

Section: Antibiotic-modifying Enzymes In M Abscessusmentioning

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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Aminoglycoside-modifying enzymes determine the innate susceptibility to aminoglycoside antibiotics in rapidly growing mycobacteria

Abstract: Our findings point to AME as important determinants of AGA susceptibility in M. abscessus.

Cited by 22 publications

References 48 publications

Diagnosis and Treatment of Nontuberculous Mycobacterial Lung Disease: Clinicians' Perspectives

Diagnosis and Treatment of Nontuberculous Mycobacterial Lung Disease: Clinicians' Perspectives

Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives

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

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