Resistance genes

Resistance to Tetracyclines. The tetracyclines stiU provide inexpensive and effective treatment for several microbial infections, but the emergence of acquired resistance to this class of antibiotic has limited their clinical usehilness. Studies to define the molecular basis of resistance are underway so that derivatives having improved antibacterial spectra and less susceptibiUty to bacterial resistance may be developed. Tetracyclines are antibiotics of choice for relatively few human infections encountered in daily clinical practice (104), largely as a result of the emergence of acquired tetracycline-resistance among clinically important bacteria (88,105,106). Acquired resistance occurs when resistant strains emerge from previously sensitive bacterial populations by acquisition of resistance genes which usually reside in plasmids and/or transposons (88,106,107). Furthermore, resistance deterrninants contained in transposons spread to, and become estabUshed in, diverse bacterial species (106). 

Their strategy was firstly to identify genes conferring resistance to mitomycin upon the produdng organism, since antibiotic resistance genes are often clustered... 

That bacterial resistance predates the era of clinical use of antibiotics by several hundred millions of years is the recent result of genomic sequence data mining from antibiotic-producing microorganisms. These are supposed to be the inventors of antibiotic resistance genes which they had developed to protect themselves from the lethal action of their own antibiotics [4]. 

Over 4 decades, between 1960 and 2000, the development of new antibiotics used well characterized basic structures for partial synthetic modifications, primarily to overcome resistance by increasing the pharmacodynamic properties and, secondarily, to improve the pharmacokinetic profile of older compounds. However, bacteria rapidly responded by acquiring additional genetic alterations either as mutations or by accumulating resistance genes as part of mobile genetic elements ( integrons) on transferable resistance plasmids. 

Shaw KJ, Rather PN, Hare RS et al (1993) Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes. Microbiol Mol Biol Rev 57 138-163... 

Bacteria can develop resistance to antimicrobial agents as a result of mutational changes in the chromosome or via the acquisition of genetic material (resistance genes carried on plasmids or transposons or the recombination of foreign DNA into the chromosome) (Fig. 2). 

Microbial Resistance to Drugs. Figure 2 Bacterial cells can obtain resistance genes in three ways ... 

Accessory DHPS enzymes confer resistance to sulfonamides. Two different types encoded by the genes sull (located on transposons) and sulll (located on plasmids) have been described. These resistance determinants are often genetically linked to trimethoprim resistance genes. Therefore, the combination of sulfonamide antibiotics with trimethoprim does not prevent resistance selection. 

Transposons are mobile DNA elements (sizes 2.5-23 kbp) that move from one place to another in the chromosome or onto extrachromosomal genetic elements within the same cell. They are flanked by inverted repeats at then-ends and encode among other proteins a transposase that is needed for the transposition process. Resistance genes in the transposon are often parts of integrons. These are structures that cany an integrase responsible for the insertion of the resistance gene cassettes into the integron. 

Multidmg Resistance Multidrug Resistance Gene Multiple Sclerosis... 

Kioka, N., Hosokawa, N., Komano, T., Hiiayoshi, H., Nagat, K., Ueda, K. (1992). Quercetin, a bioflavonoid, inhibits the increase of human multi-drug resistance gene (MDRI) expression caused by arsenite. FEES Lett. 301, 307-309. 

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. 

Plasmids have the ability to transfer within and between species and can therefore be acquired from other bacteria as well as a consequence of cell division. This property makes plasmid-acquired resistance much more threatening in terms ofthe spread of antibiotic resistance than resistance acquired due to chromosomal mutation. Plasmids also harbour transposons (section 2.1.3), which enhances their ability to transfer antibiotic resistance genes. 

Resistance may also be chromosomally mediated, t Multiple resistance genes may be carried on a transposon. 

Fig. 9.4 Organization of glycopeptide-resistance genes in transposon Tnl546. IR, invested repeats HPK, histidine protein kinase TcR, low level teicoplanin resistance.

The origins of the glycopeptide-resistance genes are unknown and share little homology with genes found in intrinsically glycopeptide-resistant organisms. 

Davies J. (1994) Inactivation of antibiotics and the dissemination of resistance genes. Science, 264, 375-382. 

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