Plasmid-mediated resistance

B. Overproduction (A) of PABA is one of the resistance mechanisms of sulfonamides. Changes in the synthesis of DNA gyrases (B) is a well-described mechanism for quinolone resistance. Plasmid-mediated resistance (C) does not occur with quinolones. An active efflux system for transport of drug out of the cell has been described for quinolone resistance, but it is not plasmid mediated. Inhibition of structural blocks (D) in bacterial cell wall synthesis is a basic mechanism of action of p-lactam antibiotics. Inhibition of folic acid synthesis (E) by blocking different steps is the basic mechanism of action of sulfonamides. 

This resistance, inducible by low concentrations of dalbaheptides, is plasmid mediated and is transferable. Concomitant with the induction of resistance is the appearance or increased expression of a protein having a molecular weight of either 39,500 or 39,000. The enzymatic activity of this material has been postulated (112). Although the mechanism of resistance induction by dalbaheptides is unknown, different dalhabaheptides have different induction capacity. Vancomycin (39) is the most powerful inducer teicoplanin is a very weak inducer. 

Bacteria produce chromosomady and R-plasmid (resistance factor) mediated P-lactamases. The plasmid-mediated enzymes can cross interspecific and intergeneric boundaries. This transfer of resistance via plasmid transfer between strains and even species has enhanced the problems of P-lactam antibiotic resistance. Many species previously controded by P-lactam antibiotics are now resistant. The chromosomal P-lactamases are species specific, but can be broadly classified by substrate profile, sensitivity to inhibitors, analytical isoelectric focusing, immunological studies, and molecular weight deterrnination. Individual enzymes may inactivate primarily penicillins, cephalosporins, or both, and the substrate specificity predeterrnines the antibiotic resistance of the producing strain. Some P-lactamases are produced only in the presence of the P-lactam antibiotic (inducible) and others are produced continuously (constitutive). 

Other pseudomonic acids (B, C, D) are also produced. Mupirocin is active predominantly against staphylococci and most streptococci, but Enterococcus faecalis and Gramnegative bacilli are resistant There is also evidence of plasmid-mediated mupirocin resistance in some chnical isolates of Staph, aureus. 

Chromosomally mediated resistance only Plasmid-mediated resistance Transposonst... 

Chromosomal and plasmid-mediated resistance to the sulphonamides has been described... 

Plasmid-mediated resistance to silver salts is of particular importance in the hospital... 

Bouanchaud DH, Hellio R, Bieth G, et al. 1975. Physical studies of a plasmid mediating tetracycline resistance and hydrogen sulfide production in Escherichia coli. Mol Gen Genet 140(4) 355-359. 

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... 

Strahilevitz J, Jacoby GA, Hooper DC et al (2009) Plasmid-mediated quinolone resistance a multifaceted threat. Clin Microbiol Rev 22(4) 664—689... 

Ozgumus OB, Sandalli C, Sevim A et al (2009) Class 1 and class 2 integrons and plasmid-mediated antibiotic resistance in coliforms isolated from ten rivers in northern Turkey. J Microbiol 47(l) 19-27... 

Cummings DE, Archer KF, Arriola DJ et al (2011) Broad dissemination of plasmid-mediated quinolone resistance genes in sediments of two urban coastal wetlands. Environ Sci Technol... 

Two mechanisms of resistance have been discovered with respect to fluoroquinolones a change in subunits A of DNA-gyrase, and reduced permeability of the outer membrane of the bacteria. Resistance is mediated by chromosomes, and not plasmids in the bacteria. The development of resistance while using the drugs is very rarely observed. 

Resistance can occur via plasmid-mediated meth-ylation of the receptor site which reduces the binding of the macrolide. Also plasmid-mediated esterase activity, especially in coliform bacteria, can inactivate the macrolides. 

Clindamycin is a chlorine-substituted derivative of lincomycin. However it is more potent and is better absorbed from the gastrointestinal tract and has therefore replaced lincomycin in most situations. Clindamycin is in principle a bacteriostatic agent. Its indications are mainly limited to mixed anaerobic infections. As mentioned above it has a similar mechanism of action as erythromycin. It selectively inhibits bacterial protein synthesis by binding to the same 50s ribosomal subunits. Erythromycin and clindamycin can interfere with each other by competing for this receptor. Also cross-resistance with erythromycin frequently occurs. Resistance is rather chromosomal rather than plasmid mediated and is especially found in cocci and Clostridium difficile. 

Chloramphenicol is able to inhibit the peptidyl transferase reaction and so bacterial protein synthesis by binding reversibly to the 50s ribosomal subunit. Resistance can occur due to the plasmid-mediated enzyme chloramphenicol acetyltransferase which inactivates the drug by acetylation. Such resistance is often a part of plasmid-mediated multidrug resistance. Resistance can also occur by an altered bacterial permeability. However in most instances resistance to chloramphenicol only develops slowly and remains partial. 

Robicsek A, Jacoby GA, Hooper DC. The worldwide emergence of plasmid-mediated quinolone resistance. Lancet Infect Dis 2006 6-10 629-40. 

Resistance What the pathogen does to the drug. For example, some strains of Pseudomonas aeruginosa produce a plasmid-mediated adeny-lase that inactivates gentamicin by chemically altering its structure. 

Resistance to the sulfonamides can be the result of decreased bacterial permeability to the drug, increased production of PABA, or production of an altered dihydropteroate synthetase that exhibits low affinity for sulfonamides. The latter mechanism of resistance is plasmid mediated. Active efflux of the sulfonamides has also been reported to play a role in resistance. The inhibitory effect of the sulfonamides also can be reversed by the presence of pus, tissue fluids, and drugs that contain releasable PABA. 

Resistance occurs as the result of one or more alterations in the cellular metabolism of the bacteria both mutation and plasmid-mediated resistance occurs. These changes, which can be irreversible, include alterations in the physical or enzymatic characteristics of the enzyme or enzymes that metabolize PABA and participate in the cellular synthesis of tetrahydrofolic acid. The appearance of alternative pathways for PABA synthesis within the bacteria or the development of an increased capacity to inactivate or eliminate the sulfonamide also may contribute to bacterial cell resistance. Bacteria that can use preformed folate are not inhibited by sulfonamides. 

The frequency of bacterial aminoglycoside resistance encountered in clinical practice has remained nearly constant over the past 2 decades. Of the three recognized mechanisms of resistance that occur in aerobic gram-negative bacteria, plasmid-mediated expression of enzymes that acetylate, adenylate, or phosphorylate the aminoglycosides is the most important. Ring one is the primary target of these enzymes. 

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 . 

---