Drug resistance aminoglycoside antibiotics

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. 

Smith CA, Baker EN (2002) Aminoglycoside antibiotic resistance by enzymatic deactivation. Curr Drug Targets Infect Disord 2 143-160... 

Development of resistance to rifaximin is primarily due to a chromosomal one-step alteration in the drug target, DNA-dependent RNA polymerase. This differs from the plasmid-mediated resistance commonly acquired by bacteria to aminoglycoside antibiotics such as neomycin... 

New concepts in the strategy of the synthesis of drugs rarely appear, such as from the observation that microorganisms often get resistance from enqrmes that inactivate the drug through phosphorylation. To avoid the problem, the aminoglycoside antibiotic kanamycin A was modified in a way that it was re-obtained whenever it was modified by the microorganism resistance enzymes (Haddad 1999). 

Structures of several important aminoglycoside antibiotics. Ring II is 2-deoxystreptamine. The resemblance between kanamycin and amikacin and between gentamicin, netilmicin, and tobramycin can be seen. The circled numerals on the kanamycin molecule indicate points of attack of plasmid-mediated bacterial transferase enzymes that can inactivate this drug. , , and , acetyltransferase , phosphotransferase , adenylyltransferase. Amikacin is resistant to modification at , , , and . 

The spectinomycins (O Fig. 20) have a fused three-ring system which consists of a 4,5-disub-stituted actinamine and an ulose. Spectinomycin is produced by Streptomyces spectabilis and Streptomyces flavopersius. It has been clinically used for treatment of the gonorrhea infection. A related structure has been discovered with spenolimycin which was isolated from the culture filtrate of Streptomyces gilvospiralis. Efforts have been directed toward semisynthetic aminoglycoside antibiotics to treat multi-drug resistant bacteria [94]. 

However, the newer fluoroquinolone derivatives show superior activity against Enterobacteriaceae and Ps. aeruginosa, and their spectrum also includes staphylococci but not streptococci. Extensive studies with norfloxacin have demonstrated that its broad spectrum, high urine concentration and oral administration make it a useful drug in the treatment of urinary infections. Ciprofloxacin may be used in the treatment of organisms resistant to other antibiotics it can also be used in conjunction with a p-lactam or aminoglycoside antibiotic, e.g. when severe neutropenia is present. 

This RNA-paromomycin structure also explains a number of features that help show why modification of the aminoglycoside antibiotic by the resistance enzymes prevents the modified drug from binding to the ribosomal site. These features are as follows. 

PJL Daniels. Aminoglycoside Antibiotics, Drug Action and Drug Resistance in Bacteria, vol. 2. Baltimore University Park Press, 1975, pp 77-111. 

---