Aminoglycoside antibiotics, resistance mechanism

Drug resistance in the defined sense, however, is not always the reason for treatment failures. The formation of biofilms may be as well regarded as a resistance mechanism. Cells within such a film withstand the antibiotic treatment. Some antibiotics (e.g. the aminoglycoside tobramycin) penetrate only slowly into the film. A further explanation is the existence of cells living in a non-growing, protected phenotypic state. 

Further studies on the mechanism of resistance of aminoglycoside antibiotics focused on resistance genes existing in antibiotic-producer strains (mainly by Drs. Y. Okami and Kunimoto Hotta), and gradually clarified the relationship between the antibiotic-producing and -regulating mechanism. During this search, indolizomycin (1984) was discovered by cell fusion of two kinds of strains. 

Biochemical mechanism of resistance to aminoglycosidic antibiotics, H. Umezawa, Adv. Carbohydr. Chem. Biochem., 30 (1974) 183-225. 

Aminoglycoside efflux is a significant mechanism of aminoglycoside resistance in bacteria of the genera Pseudomonas, Burkholderia, and Stenotrophomonas. There are five classes of transmembrane efflux systems associated with antibiotic resistance however, the resistance nodulation division (RND) family is the predominant class (Table 3.1). ... 

Bacterial Resistance Mechanisms. The most common resistance mechanism involves the inactivation of the aminoglycoside by reactions cat alyzed by plasmid borne enzymes. In general, amikacin and isepam icin tend to be least susceptible to inactivation by this mechanism, while netilmicin and dibekacin are intermediate and gentamicin and tobramycin are most susceptible. Less common resistance mechanisms include decreased affinity for the antibiotic by the bacterial ribosome, and decreased rate of transport into the bacterial cytoplasm. 

The resistance mechanisms that cause the inactivation of penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines do not apply to fluoroquinolones, and there is therefore no cross-resistance between quinolones and other antibiotics. 

The evolution of MRSA strains is not fully understood, but the same mechanisms of mutation and gene transfer that exist in other species provide a likely reason. The emergence of gentamicin resistance plasmids illustrates the evolutionary potential of translocatable elements [186], MRSA strains which are also resistant to this aminoglycoside antibiotic are referred to as MGRSA. This evolutionary progression is also responsible for the formation of the -lactamase-heavy metal resistant plasmids [250]. Some MRSA isolates are penicillin-resistant by virtue of the enzyme /J-lactamase, which pre-dates the use of /8-lactams [251], However, the spread of the phenotype has probably arisen as a result of selection caused by the widespread usage of methicillin in hospitals. 

Phosphorylation is a common mechanism resulting in resistance to the aminoglycoside antibiotics. This chemical strategy also has been associated with resistance to the macrolides such as erythromycin, the tuberactinomycins such as viomycin, and chloramphenicol. The aminoglycoside kinases share 3D structural similarity with the Ser/Thr/Tyr protein kinase family (36), and the conservation of kinase signature sequences in macrolide... 

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