Transferable Multidrug-Resistance Plasmid Carrying a Novel Macrolide-Clindamycin Resistance Gene, erm (50), in Cutibacterium acnes

Abstract

Antimicrobial-resistant Cutibacterium acnes strains have emerged and disseminated throughout the world. The 23S rRNA mutation and erm(X) gene are known as the major resistance determinants of macrolides and clindamycin in C. acnes. We isolated eight high-level macrolide-clindamycin-resistant C. acnes strains with no known resistance determinants, such as 23S rRNA mutation and erm(X), from different acne patients in 2008 between 2013 and 2015. The aim of this study was to identify the novel mechanisms of resistance in C. acnes. Whole-genome sequencing revealed the existence of a plasmid DNA, denoted pTZC1 (length, 31,440 bp), carrying the novel macrolide-clindamycin resistance gene erm(50) and tetracycline resistance gene tet(W). pTZC1 was detected in all C. acnes isolates (eight strains) exhibiting high-level macrolide-clindamycin resistance, with no known resistance determinants (MIC of clarithromycin, ≥256 μg/ml; clindamycin, ≥256 μg/ml). Transconjugation experiments demonstrated that the pTZC1 was horizontally transferred among C. acnes strains and conferred resistance to macrolides, clindamycin, and tetracyclines. Our data showed, for the first time, the existence of a transferable multidrug-resistant plasmid in C. acnes. Increased prevalence of this plasmid will be a great threat to antimicrobial therapy for acne vulgaris.

A Janus-Faced Bacterium: Host-Beneficial and -Detrimental Roles of Cutibacterium acnes

“…In addition, erm(X), encoding a RNA methylase that mediates resistance to clindamycin, has been identified on a mobile genetic element (Ross et al, 2002). Interestingly, a novel mobile genetic element of C. acnes was recently identified, conferring resistance to macrolides, clindamycin, and tetracyclines: the plasmid pTZC1 carries a novel macrolide-clindamycin resistance gene, erm(50), as well as a tetracycline resistance gene, tet(W) (Aoki et al, 2020). Resistant strains of C. acnes often belong to the acneassociated types, i.e., phylotypes IA 1 (SLST types A and C) and IA 2 (SLST type F) (Lomholt and Kilian, 2014;Nakase et al, 2017;Sheffer-Levi et al, 2020).…”

“…This review will often refer to the main six phylotypes (and the 10 SLST types) and their distinct associations with health and disease. Apart from core genome differences, the accessory genome of C. acnes is relatively small but comprises elements such as a linear plasmid (designated p15.1.R1 or pIMPLE-HL096PA1, encoding a conjugation apparatus and a tight adherence pili locus) and a circular plasmid (designated pTZC1, encoding genes conferring resistance to macrolides, clindamycin and tetracycline) (Tomida et al, 2013;Davidsson et al, 2017;Aoki et al, 2020). In addition, around 60 other regions that are not part of the core genome can be identified in the pan-genome of C. acnes; these non-core genes are often, but not exclusively, phylotype-specific, and code for a variety of functions such as different transport systems, bacteriocin synthesis, resistance to heavy metals and antibiotics, restriction modification systems, CRISPR/cas systems, (cryptic) prophages, transposases, carbohydrate and amino acid processing enzymes, and many so far unknown functions (Brüggemann et al, 2012;Tomida et al, 2013;.…”

Genomic Analysis of Cutibacterium acnes Strains Isolated from Prosthetic Joint Infections

“…A comparative analysis of the plasmids using the tool BRIG ( Figure 2 ) showed a deletion of approximately 10 kb in the plasmid of the C1 strain ZH8; this deletion was not detected before in any known plasmid sequence. Another plasmid, designated pTZC1, conferring resistance to macrolides, clindamycin, and tetracyclines, which has been found in C. acnes strains isolated in Japan, could not be identified in any of the 16 strains sequenced here [ 40 ].…”

Potential Target Site for Inhibitors in MLSB Antibiotic Resistance

“…From the Erm family, a total of 44 sequences were aligned, where 41 of them could be retrieved from CARD (comprehensive antibiotic resistance database; [ 22 ]) and ErmI [ 23 , 24 ], Erm50 [ 25 ] and Erm51 [ 26 ] were added to them. To the authors’ knowledge, these are all Erm proteins reported at the time of submission of the paper.…”

“…The expression vector (pHJJ105) and E. coli strain ( E. coli HJJ105) overexpressing the wild-type ErmS was obtained in previous studies [ 25 , 34 ]. Site-directed mutagenesis was carried out by a sequential PCR method designated overlap extension PCR [ 47 ].…”