Macrolide Resistance in Mycobacteria

Abstract

The genus Mycobacterium contains two of the most important human pathogens, Mycobacterium tuberculosis and Mycobacterium leprae, the etiological agents of tuberculosis and leprosy, respectively. Other mycobacteria are mostly saprophytic organisms, living in soil and water, but some of them can cause opportunistic infections. The increasing incidence of tuberculosis as well as infections with non-tuberculous mycobacteria (NTM) in immuno-compromised patients has renewed interest in molecular mechanisms of drug resistance in these pathogens. Mycobacteria show a high degree of intrinsic resistance to most common antibiotics. For instance, species from the M. tuberculosis complex (MTC) are intrinsically resistant to macrolides. Nevertheless, some semi-synthetic macrolides as clarithromycin, azithromycin and most recently the ketolides, are active against NTM and widely used for infection treatment. However, shortly after the introduction of these new drugs, resistant strains appeared due to mutations affecting the macrolide target, the ribosome. The mycobacterial cell wall is considered to be a major factor in promoting the natural resistance of mycobacteria to various antibiotics. However, recent data show that specific macrolide resistance determinants (erm genes) are present in some species.This mini-review summarizes the current knowledge on the natural and acquired macrolide resistance in mycobacteria, gives an overview of potential mechanisms implicated in the intrinsic resistance and of macrolide resistance determinants in mycobacteria.

Impact of Azithromycin Resistance Mutations on the Virulence and Fitness of Chlamydia caviae in Guinea Pigs

“…(6). Note that the A 2058 G substitution in 23S rRNA, which is the most common macrolide resistance mutation encountered (10,35), was found in none of the 30 strains with spontaneous mutations conferring Azm r isolated previously for C. psittaci 6BC and in only 1 out of 45 independent mutants of C. caviae analyzed in this study, i.e., SP 7 . It is tempting to speculate that SP 7 possesses genetic factors such as an intragenic or extragenic compensatory mutation to balance the cost of this mutation to chlamydiae (8,20).…”

Ancestral antibiotic resistance in Mycobacterium tuberculosis

“…3). The whiB7-dependent set of eight transcripts includes three genes that may provide intrinsic antibiotic resistance: tap (Rv1258c), encoding an efflux pump that confers low-level resistance to aminoglycosides and tetracycline (33); an unstudied ORF encoding a putative macrolide transporter (Rv1473) with an ATPbinding cassette; and erm (Rv1988), homologous to ribosomal methyltransferases and conferring MLS (macrolide, lincosamide, and streptogramin) resistance by modification of 23S rRNA (7,34). Although the whiB7 regulon may include unrecognized antibiotic resistance determinants, other functions were also suggested.…”

“…However, Jarlier and Nikaido (4) have also pointed out that this permeability barrier is insufficient to fully explain the high levels of drug resistance in Mycobacterium, suggesting that there must be synergistic systems effective against drugs that penetrate this barrier. Indeed, several mycobacterial genes not involved in outer envelope assembly confer resistance to specific, broadspectrum antibiotics (6)(7)(8).…”

Frequency of Development and Associated Physiological Cost of Azithromycin Resistance in Chlamydia psittaci 6BC and C. trachomatis L2

“…We also sequenced the rplD and rplV genes, coding for ribosomal proteins L4 and L22, respectively. These genes represent two other known mutational targets for macrolide resistance (12). In all 10 isolates, one single mutation, C 196 to A, was found in rplD, creating to a Gln-to-Lys alteration at position 66 in the C. trachomatis L2 ribosomal protein L4.…”