Macrolide antibiotics drug resistance

Poehlsgaard J, Douthwaite S. Macrolide antibiotic interaction and resistance on the bacterial ribosome. Curr Opin Investig Drugs. 2003 4 140-148. 

Kim, Y. J., Furihata, K., Shimazu, A., Furihata, K., and Seto, H. (1991). Isolation and structural elucidation of sekothrixide, a new macrolide effective to overcome drug-resistance of cancer cell. J. Antibiot. 44, 1280-1282. 

It is widely accepted that MLS antibiotics inhibit protein synthesis by binding to closely related sites on the 508 subunit of the 70S ribosome of bacteria [4], despite being structurally different from each other (see Figs. 1 and 2 in a later section). That is the reason why, when inducible resistant Staphylococcus aureus cells are exposed to a low concentration of the drug (0.05 tg erythromycin/ml - 6.8 x 10 M), they show resistance against not only erythromycin but also other macrolide antibiotics as well as lincosamide and type B streptogramin antibiotics. Erythromycin has been widely used and has been the object of extensive molecular and biological studies. 

In this chapter, the molecular-biological mode of action of macrolide antibiotics and the biochemical and genetic mechanisms of resistance to MLS antibiotics are reviewed. Based on a recent X-ray crystallographic study on a 50S ribosomal subunit from Haloarcula marismortui and the finding of intracellular macrolide accumulation, the mode of action from the viewpoint of a new hypothetical concept, deposition binding, and mechanisms of drug resistance in clinically isolated bacteria are discussed. In addition, recent major developments in macrolide antibiotics are briefly described. 

Genes for resistance are not new creations. There seems to be no exception to the rule in genes responsible for resistance to macrolide antibiotics. In fact, many kinds of clinical isolates that carry resistant determinant(s) to macrolide antibiotics rarely develop the same mechanism as drug-resistant mutants, which arise in vitro from treatment with mutagens. 

Assuming that the major accumulation of erythromycin in S. aureus cells is determined by uptake dependent on the amounts of ribosome present in the cells, these observations of drug accumulation can be easily accounted for. As described in a previous section, erythromycin molecules can bind to ribosome at a certain equilibrium state expressed as a dissociation constant [39]. For example, on the supposition that an intracellular concentration of erythromycin increases by 30 times the level of that in an extracellular medium (1 pg/ml), the nonprotonated molecules of erythromycin (p T = 8.8) are able to occupy no more than 1% of a drug concentration present in S. aureus cell. That is why it is expected that intracellular pH would be 6.8 or less [200] and that erythromycin (even as a free base) with p T = 8.8 is one of the most water-soluble (i.e., deposition-resisting) drugs in the macrolide antibiotics (Table I). 

Nelfinavir mesylate is a peptidomimetic drug that is effective in HIV-1 and HIV-2 wild-type and ZDV-resistant strains, with median effective dose concentrations ranging from 9 to 60 nM (95% effective dose, 0.04 mg/mL) (98). After IV administration, the elimination half-life of nelfinavir was approximately 1 hour. In combination with D4T, nelfinavir reduced HIV viral load by approximately 98% after 4 weeks. It is well tolerated when used with azole antifungals (ketoconazole, fluconazole, or itraconazole) or macrolide antibiotics (erythromycin, clarithromycin, or azithromycin) however, it causes diarrhea and other side effects common to nonnucleoside drugs. Following oral administration, nelfinavir peak levels in plasma ranged from 0.34 mg/mL (10 mg/kg in the dog) to 1.7 mg/mL (50 mg/kg in the rat). In the dog, nelfinavir was slowly absorbed, and bioavailability was 47%. The drug appeared to be metabolized in the liver, and the major excretory route was in feces. 

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. 

Drug action and drug resistance in bacteria Macrolide antibiotics and lincomycin". Ed. S. Mitsuhashi, University Park Press, Baltimore, Maryland. 1972. 

Some streptococci have developed a different mechanism of acquired resistance to penicillin drugs. These bacteria have altered transpeptidases (also known as penicillin-binding proteins) that no longer bind penicillin, and thus peptidoglycan synthesis is not disrupted. This mechanism of resistance is found in Streptococcus pneumoniae. Estimates of penicillin-resistant S. pneumoniae in the United States range from 25% to 66%, including strains recovered from ocular and periocular infections. Many isolates of penicillin-resistant S.pneumoniae also are resistant to the cephalosporins, macrolides, and the older fluoroquinolones. Use of alternative antibiotics such as vancomycin is necessary for infections caused by penicillin-resistant isolates. 

As this category of penicillins was used for treatment, S. aureus and S. epidermidis became resistant to them through the production of altered penicillin-binding proteins. These strains of staphylococci are called methicillin resistant, which denotes resistance not only to all penicillinase-resistant penicillins but to all penicillin drugs. Methicillin-resistant staphylococci have become a major problem in treatment because they are also resistant to the cephalosporins, aminoglycosides, and macrolides. For this reason vancomycin, a more toxic antibiotic, is the drug of choice for these organisms. 

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