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Aminoglycoside resistance

Aminoglycosides (Streptomycin, kanamycin, tobramycin, amikacin,...) are compounds that are characterized by the presense of an aminocyclitol ring linked to aminosugars in their structure. Their bactericidal activity is attributed to the irreversible binding to the ribosomes although their interaction with other cellular structures and metabolic processes has also been considered. They have a broad antimicrobial spectrum. They are active against aerobic and facultative aerobic Gram-negative bacilli and some Gram-positive bacteria of which staphylococci. Aminoglycosides are not active against anaerobes and rikettsia. Spectinomycin which is an aminocyclitol devoided of aminosugars is by extension included in the familiy of aminoglycosides. It also differs from them by its bacteriostatic ativity and by its way of action. Spectinomycin acts on protein synthesis during the mRNA-ribosome interaction and it does not lead to mistranslation like aminoglycosides do.
Three mechanisms of resistance have been recognized, namely ribosome alteration, decreased permeability, and inactivation of the drugs by aminoglycoside modifying enzymes. The latter mechanism is of most clinical importance since the genes encoding aminoglycoside modifying enzymes can be disseminated by plasmids or transposons.
Ribosome alteration
High level resistance to streptomycin and spectinomycin can result from single step mutations in chromosomal genes encoding ribosomal proteins: rpsL (or strA), rpsD (or ramA or sud2), rpsE (eps or spc or spcA). Mutations in strC (or strB) generate a low-level streptomycin resistance.
Decreased permeability
Absence of or alteration in the aminoglycoside transport system, inadequate membrane potential, modification in the LPS (lipopolysacchaccarides) phenotype can result in a cross resistance to all aminoglycosides.
Inactivation of aminoglycosides
These enzymes are classified into three major classes according to the type modification: AAC (acetyltransferases), ANT (nucleotidyltransferases or adenyltransferases), APH (phosphotransferases). This classification was extensively reviewed by Shaw et al. (1993).

Commonly used aminoglycoside resistance markers in molecular biology

ant(3'')-Ia (synonyms: aadA, aad(3'')(9))confers resistance to streptomycin and spectinomycin. The gene has been found in association with several transposons (Tn7, Tn21, ...) and is ubiquitous among gram-negative bacteria.

(synonyms: aphA-2, nptII) confers resistance to Km (Kanamycin), Neo (Neomycin), Prm (Paromomycin), Rsm (Ribostamycin), But (Butirosin), GmB (GentamycinB). This gene is rarely found in clinical isolates. aph(3')-II is associated with transposon Tn5 and observed in gram-negative bacteria and Pseudomonas sp. However, its relative abundance in environmental KanR isolates seems to be low (Recorbet et al., 1992; Leff et al., 1993; Smalla et al., 1993).

aph(3')-III (synonyms: nptIII) confers resistance to Km (Kanamycin), Neo (Neomycin), Prm (Paromomycin), Rsm (Ribostamycin), Lvdm (Lividomycin), But (Butirosin), GmB (GentamycinB). Amk (Amikacin) and Isp (Isepamicin) are also modified in vitro, but according to the susceptibility standards established by NCCLS resistance is only expressed at a low level by many strains. aph(3')-III is commonly distributed among gram-positive bacteria but has also been observed in Campylobacter spp.
nptIII is not frequent in molecular biology but can be found on some Agrobacterium vectors for plant transformation (Bevan, 1984).

Hot links

* Aminoglycoside Modifying Enzymes (Copyrights © by WARN Development)

* Aminoglycoside antibacterials (Copyrights © by Purdue Research Foundation)

* Aminoglycosides (link to the University of Winconsin Hospital)

Selected reading

Bevan, M. 1984. Binary Agrobacterium vectors for plant transformation. Nucleic Acids Res. 12:8711-8721.

Flamm, R. K., K. L. Phillips, F. C. Tenover, and J. J. Plorde. 1993. A survey of clinical isolates of Enterobacteriaceae using a series of DNA probes for aminoglycoside resistance genes. Mol. Cell Probes. 7:139-144. Review.

Leff, L. G., J. R. Dana, J. V. Mc Arthur; and L. J. Shimkets. 1993. Detection of Tn5-like sequences in kanamycin-resistant stream bacteria and environmental DNA. Appl. Environ. Microbiol. 59:417-421.

Miller, G. H., F. J. Sabatelli, L. Naples, R. S. Hare, and K. J. Shaw. 1995. The changing nature of aminoglycoside resistance mechanisms and the role of isepamicin--a new broad-spectrum aminoglycoside. The Aminoglycoside Resistance Study Groups. J. Chemother. 7 Suppl 2:31-44.

Miller, G. H., F. J. Sabatelli, R. S. Hare, Y. Glupczynski, P. Mackey, D. Shlaes, K. Shimizu, and K. J. Shaw. 1997. The most frequent aminoglycoside resistance mechanisms--changes with time and geographic area: a reflection of aminoglycoside usage patterns? Aminoglycoside Resistance Study Groups. Clin. Infect. Dis. 24 Suppl 1:S46-S62.

Recorbet, G., A. Givaudan, C. Steinberg, R. Bally, P. Normand, and G. Faurie. 1992. Tn5 to assess soil fate of genetically marked bacteria: screening for aminoglycoside resistance advantage and labelling specificity. FEMS Microbiol. Ecol. 86:187-194. No abstract available.

Rice, E. W., J. W. Messer , C. H. Johnson, and D. J. Reasoner. 1995. Occurrence of high-level aminoglycoside resistance in environmental isolates of enterococci. Appl. Environ. Microbiol. 61:374-376.

Shaw, K.J., P.N. Rather, R.S. Hare, and G.H. Miller. 1993. Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes. Microbiol. Rev. 57:138-163. Review.

Smalla, K., L. S. van Overbeek, R. Pukall, and J. D. van Elsas. 1993. Prevalence of nptII and Tn5 in kanamycin-resistant bacteria from different environments. FEMS Microbiol. Ecol. 13:47-58. No abstract available.

Swenson, J. M., M. J. Ferraro, D. F. Sahm, N. C. Clark, D. H. Culver, and F. C. Tenover. 1995. Multilaboratory evaluation of screening methods for detection of high-level aminoglycoside resistance in enterococci. National Committee for Clinical Laboratory Standards Study Group on Enterococci. J. Clin. Microbiol. 33:3008-3018.

The aminoglycoside Resistance Study Group. 1994. Resistance to aminoglycosides in Pseudomonas.Trends Microbiol. 2:347-352.

The Aminoglycoside Resistance Study Groups. 1995. The most frequently occurring aminoglycoside resistance mechanisms--combined results of surveys in eight regions of the world. J. Chemother. 7 Suppl 2:17-30.

van de Klundert, J. A., and J. S. Vliegenthart. 1993. Nomenclature of aminoglycoside resistance genes: a comment. Antimicrob. Agents Chemother. 37:927-928. No abstract available.

van Elsas and K. Smalla. 1995. Antibiotic (kanamycin and streptomycin) resistance traits in the environment. Presented at the Workshoop on "Key Biosafety Aspects of Genetically modified Organisms. Braunschweig, Germany.

Khan, M. S., and P. Maliga. 1999. Fluorescent antibiotic resistance marker for tracking plastid transformation in higher plants. Nat. Biotechnol. 17(9):910-915.

Schmitz, F. J., J. Verhoef, and A. C. Fluit. 1999. Prevalence of aminoglycoside resistance in 20 European university hospitals participating in the European SENTRY Antimicrobial Surveillance Programme. Eur. J. Clin. Microbiol. Infect. Dis. 18(6):414-421.

Recht, M. I., S. Douthwaite, and J. D.Puglisi. 1999. Basis for prokaryotic specificity of action of aminoglycoside antibiotics. EMBO J. 18(11):3133-3138.

Mingeot-Leclercq, M. P., Y. Glupczynski, and P. M. Tulkens. 1999. Aminoglycosides: activity and resistance. Antimicrob. Agents Chemother. 43(4):727-737. No abstract available.


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