Efflux Pumps Contribute to Intrinsic Clarithromycin Resistance in Clinical, Mycobacterium abscessus Isolates

Qi Guo; Jianhui Chen; Shaoyan Zhang; Yuzhen Zou; Yongjie Zhang; Dongdong Huang; Zhemin Zhang; Bing Li; Haiqing Chu

doi:10.2147/IDR.S239850

Efflux Pumps Contribute to Intrinsic Clarithromycin Resistance in Clinical, Mycobacterium abscessus Isolates

Infect Drug Resist. 2020 Feb 12:13:447-454. doi: 10.2147/IDR.S239850. eCollection 2020.

Authors

Qi Guo^{1

2}, Jianhui Chen^{1

2}, Shaoyan Zhang¹, Yuzhen Zou^{1

2}, Yongjie Zhang^{1

2}, Dongdong Huang¹, Zhemin Zhang¹, Bing Li¹, Haiqing Chu^{1

3}

Affiliations

¹ Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, People's Republic of China.
² Tongji University School of Medicine, Shanghai 200092, People's Republic of China.
³ Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, People's Republic of China.

Abstract

Purpose: The emergence of clarithromycin resistance is a challenge in treating Mycobacterium abscessus infections. Known mechanisms that contribute to intrinsic clarithromycin resistance focus on rrl gene-related mutations, but resistant clinical isolates often exhibit an inconsistent rrl genotype.

Patients and methods: In this study, 194 clinical Mycobacterium abscessus isolates were collected from patients with lung infections and the whole genome of each isolate was sequenced. A comprehensive examination of the molecular mechanisms underlying intrinsic clarithromycin resistance was performed, combining MIC determination, comparative genome sequence analysis and qRT-PCR.

Results: Of the 194 isolates, 13 (6.7%) were clarithromycin resistant; only seven of these harbored a rrl 2270/2271 mutation. The remaining six resistant isolates did not exhibit a specific resistance-associated mutation in the clarithromycin target-site genes, rrl, rplC, rplD and rplV, or in the rrl modification gene erm(41). qRT-PCR analysis showed that the increased expression of the efflux pump genes, MAB_2355c, MAB_1409c and MAB_1846, as well as their positive regulatory gene whiB7, consistently correlated with increased clarithromycin resistance. The presence of efflux pump inhibitors significantly decreased the MIC of clarithromycin for nonsusceptible isolates, especially the intrinsic resistant isolates that exhibited no rrl 2270/2271 mutation.

Conclusion: These findings indicate that efflux pumps play a prominent role in the intrinsic resistance of M. abscessus to clarithromycin, complementing other known resistance mechanisms.

Keywords: Mycobacterium abscessus; clarithromycin resistance; efflux pumps.

Grants and funding

This work was funded by grants provided by the: National Natural Science Foundation of China (Nos. 81672063, 81971973 and 81800003), Natural Science Foundation of Shanghai Municipal Science and Technology Commission (Nos. 18ZR1431600 and 19ZR1442800), Medical Guide Program of Shanghai Science and Technology Committee (Nos.18411970600 and 19411969600), New Frontier Technology Joint Project of Municipal Hospital, Shanghai Shenkang Hospital Development Center (No. SHDC12017113), Shanghai Health and Family Planning Commission Excellent Talents Training Program (No. 2018YQ55), General Project of Shanghai Health and Family Planning Commission (201940229), and Project of Top Clinical Medicine Centers and Key Disciplines Construction in Shanghai (No. 2017ZZ02012).