Macrolide antibiotics, 16-membered resistance

Macrolides inhibit growth of bacteria by inhibiting protein synthesis on ribosomes. Bacterial resistance to macrolides is often accompanied by cross-resistance to lincosamide and sireptogramin B antibiotics (MLS-resistance), which can be either inducible or constitutive. 14-Membered... 

Macrolides inhibit growth of bacteria by inhibiting protein synthesis on ribosomes (17,415,416). Bacterial resistance to macrolides is often accompanied by cross-resistance to lincosamide and streptogramin B antibiotics (MLS-resistance), which can be either inducible or constitutive (417). 14-Membered macrolides generally induce resistance to themselves, whereas 16-membered macrolides do not consequendy, one advantage of the latter is their activity against bacteria which are inducibly resistant to erythromycin. Both 14- and 16-membered macrolides lack activity against constitutively resistant strains (387,388). 

In recent years, new resistance phenotypes (macrolide and streptogramin B antibiotics [MS] or partial macrolide and streptogramin B antibiotics [PMS], and macrolide antibiotics [M]) have been observed in elinical isolates of staphylococci and streptococci. Ross et al. [61, 125, 193] and Goldman and Capobianco [126] reported that MS-resistant strains of Staphylococcus epidermidis were resistant to 14- or 15-membered-ring macrolides and streptogramin B, but were susceptible to 16-membered-ring macrolide and lincosamide antibiotics. 

Otoguro, K. et al.. In vitro and in vivo antimalarial activities of a non-glycosidic 18-membered macrolide antibiotic, borrelidin, against drug-resistant strains of Plasmodia, J. Antibiot. (Tokyo), 56, 727, 2003. 

Another group of antibiotics that can be inactivated by hydrolysis are 14- and 15- membered macrolides [2]. Esterases cleave the lactone ring. The plasmid encoded ere genes are found in members of the Enter-obacteriaceae and increase the intrinsic resistance. Furthermore, these esterases can also be found in some isolates of erythromycin resistant staphylococci. 

Plasmid (or transposon)-encoded enzymes are thus responsible for the degradation of several different types of antibiotics. The inactivation of several /J-lactams, AGACs, 14-membered macrolides, other macrolides, lin-cosamides and streptogramis (MLS) and chloramphenicol is a major resistance mechanism it has yet to be shown that inactivation of other antibiotics falls into this category. 

The MLS (macrolides, lincosamides, streptogramins) group of antibiotics all inhibit protein synthesis by binding to the 50S ribosomal subunit. Resistance mechanisms specific to individual members occur but resistance to all may be conferred by a single mechanism that involves 23S rRNA. However, it is claimed that the quinupristin-dalfopristin combination does not demonstrate cross-resistance to other antibiotics within the MLS group or to other antibiotics. 

Most of the data on rokitamycin have been published in Japanese and Italian journals. As a propionyl ester of leucomycin, rokitamycin has an antimicrobial spectrum similar to that of erythromycin, it is especially potent against L. pneumophila, M. pneumoniae, and Chlamydia. Like other 16-membered macrolides, it is active against bacteria that are inducibly resistant to erythromycin but inactive against strains that are constitutively resistant to macrolide-lincosamide-streptogramin B antibiotics. 

On the other hand, although PMS-resistant S. aureus was first described as an inducible MS-like resistant strain [127], it was later found that the strain conferred inducible resistance to mycinamicin, a 16-membered-ring macrolide, in addition to 14-membered-ring macrolides and streptogramin type B antibiotics. Matsuoka et al. disclosed that the gene product of S. auerus msrSA including msrSA, MsrSA protein, is 98% similar to the S. epidermidis MsrA protein [45, 59, 122, 128, 197]. 

In terms of fourth-generation macrolides, the substitution of L-cladinose at C3 in erythromycin A with a keto produces ketolides, such as telithromycin (formerly HMR3647) and ABT-773, and also causes an increase in acid stability and a new characteristic different from erythromycin. For example, the semisynthetic drugs do not induce MLS resistance, unlike 14-membered-ring macrolides produced naturally by antibiotic producers [204], but they do not inhibit staphylococcal strains carrying erythromycin-induced or constitutive MLS resistance specified by the erm gene. 

Janosi, L., Nakajima, Y, and Hashimoto, H. (1990). Characterization of plasmids that confer inducible resistance to 14-membered macrolide and streptogramin type B antibiotics in Staphylococcus aureus. Microbiol. Immunol. 34, 723-735. 

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