Dataset Information

Rifaximin potentiates clarithromycin against Mycobacterium abscessus in vitro and in zebrafish.

ABSTRACT:

Background

Mycobacterium abscessus is a non-tuberculous mycobacterium (NTM) that causes chronic pulmonary infections. Because of its extensive innate resistance to numerous antibiotics, treatment options are limited, often resulting in poor clinical outcomes. Current treatment regimens usually involve a combination of antibiotics, with clarithromycin being the cornerstone of NTM treatments.

Objectives

To identify drug candidates that exhibit synergistic activity with clarithromycin against M. abscessus.

Methods

We performed cell-based phenotypic screening of a compound library against M. abscessus induced to become resistant to clarithromycin. Furthermore, we evaluated the toxicity and efficacy of the top compound in a zebrafish embryo infection model.

Results

The screen revealed rifaximin as a clarithromycin potentiator. The combination of rifaximin and clarithromycin was synergistic and bactericidal in vitro and potent in the zebrafish model.

Conclusions

The data indicate that the rifaximin/clarithromycin combination is promising to effectively treat pulmonary NTM infections.

SUBMITTER: Goh BC

PROVIDER: S-EPMC10164658 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

Rifaximin potentiates clarithromycin against <i>Mycobacterium abscessus in vitro</i> and in zebrafish.

Goh Boon Chong BC Larsson Simon S Dam Linh Chi LC Ling Yan Han Sharon YHS Chua Wei Lin Patrina WLP Abirami R R Singh Samsher S Ong Jun Long Ernest JLE Teo Jeanette W P JWP Ho Peiying P Ingham Philip W PW Pethe Kevin K Dedon Peter C PC

JAC-antimicrobial resistance 20230508 3

<h4>Background</h4><i>Mycobacterium abscessus</i> is a non-tuberculous mycobacterium (NTM) that causes chronic pulmonary infections. Because of its extensive innate resistance to numerous antibiotics, treatment options are limited, often resulting in poor clinical outcomes. Current treatment regimens usually involve a combination of antibiotics, with clarithromycin being the cornerstone of NTM treatments.<h4>Objectives</h4>To identify drug candidates that exhibit synergistic activity with clarit ...[more]

PMID: 37168836

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Project description:PurposeClarithromycin was considered the cornerstone for the treatment of Mycobacterium abscessus complex infections. Genetic resistance mechanisms have been described and many experts propose amikacin as an alternative. Nevertheless, clarithromycin has several advantages; therefore, it is necessary to identify the non-functional erm(41) allele to determine the most suitable treatment. The aims of this study were to characterize the molecular mechanisms of clarithromycin resistance in a collection of Mycobacterium abscessus complex isolates and to verify the relationship between these mechanisms and the antibiogram.Materials and methodsClinical isolates of M. abscessus complex (n = 22) from 16 patients were identified using four housekeeping genes (rpoB, secA1, sodA and hsp65), and their genetic resistance was characterized by studying erm(41) and rrl genes. Nine strains were recovered from the clinical isolates and subjected to E-test and microdilution clarithromycin susceptibility tests, with readings at 3, 7 and 14 days.ResultsWe classified 11/16 (68.8%) M. abscessus subsp. abscessus, 4/16 (25.0%) M. abscessus subsp. bolletii, and 1/16 (6.3%) M. abscessus subsp. massiliense. T28 erm(41) allele was observed in 8 Mycobacterium abscessus subps. abscessus and 3 Mycobacterium abscessus subsp. bolletii. One strain of M. abscessus subsp. bolletii had an erm(41) gene truncated and was susceptible to clarithromycin. No mutations were observed in rrl gene first isolates. In three patients, follow-up of initial rrl wild-type strains showed acquired resistance.ConclusionsMost clinical isolates of M. abscessus complex had inducible resistance to clarithromycin and total absence of constitutive resistance. Our findings showed that the acquisition of resistance mutations in rrl gene was associated with functional and non-functional erm(41) gene. Caution is needed when using erm(41) sequencing alone to identify M. abscessus subspecies. This study reports an acquired mutation at position 2057 of rrl gene, conferring medium-low clarithromycin constitutive resistance.