Plasmids, causing resistance

Duplication ofDHPS, with the second version of the enzyme being resistant to the sulphonamides, is the cause of plasmid-acquired resistance. Two different enzymes have been identified, both with lowered affinity for the antibiotic. 

Multidrug resistance (Mdr) is a serious problem in enteric and other Gramnegative bacteria [41, 71, 273-283] (Table 4.17). As distinct from plasmid-mediated resistance, described above, Mdr is a term employed to describe a resistance mechanism by genes that comprise part of the normal cell genome. These genes are activated by induction or mutation caused by some types of stress, considered below. Because the genes are ubiquitously distributed, there is no need for genetic transfer. 

Resistance to the new 4-quinolones is not a significant problem so far. Spontaneous resistance occurs in less than 10u colony-forming units. Bacterial resistance to ND in bacterial chromosomes arise by two mechanisms. One is the result of mutation of the A subunit of DNA-gyrase (see later), which causes a high level of resistance the other involves membrane alteration at the B subunit, which causes low-level resistance. The feared plasmid-mediated resistance (transfer of resistance) often seen with other antibiotics has not been encountered so far. Thus the only route for development of resistance in these drugs is by mutation. 

Bacterial resistance to sulfonamides can originate by random mutation and selection or by plasmid transfer of resistance it usually does not confer cross-resistance to other classes of antibiotics. Resistance to sulfonamide results from altered constitution of the bacterial cell that causes (I) a lower affinity for sulfonamides by dihydropteroate synthase, (2) decreased bacterial permeability or active efflux of the drug, (3) an alternative metabolic pathway for synthesis of an essential metabolite, or (4) an increased production of an essential metabolite or drug antagonist. Plasmid-mediated resistance is due to plasmid-encoded, drug-resistant dihydropteroate synthetase. 

P-Lactamases were first described in Staphylococcus aureus as factors causing resistance to penicillin (Kirby 1944). Later, the first plasmid-encoded P-lactamase, designated TEM based on the patient s name, was described in Greece from a strain of E. coli (Datta and Kontomichalou 1965). Currently, hundreds of different types of p-lactamases have been described. These enzymes are categorized based on their molecular properties (Ambler classification) or their hydrolytic pattern (Bush classification)—see Table 12.1 (Bush et al. 1995 Bush and Jacoby 2010). 

Nucleotidylation - the addition of adenylate-residues by Lnu enzymes - can also be the cause of resistance to lincosamide antibiotics in staphylococci and enterococci. A plasmid encoded ADP-ribosylating transferase (Arr-2) that leads to rifampicin resistance has been detected in various Enterobacteriaceae as well as in Pseudomonas aeruginosa. 

Antibiotics are routinely added to animal feed in conventional agriculture. This can have various effects on humans. Direct transmission of antibiotic residues in animal products to people may cause direct toxicity, i.e. allergies, or lead to the emergence of resistant strains of bacteria. Another threat is antibiotic-resistant forms of bacteria harmful to mankind that might appear in animals and pass from them to humans (Smith 1974), or may impart resistance to other bacteria by plasmid or transposon interchange (Franco et al. 1990). The resulting dmg-resistant and harmful micro-organisms can then not be treated successfully (Silverstone 1993). 

Use of penicillin and the tetracyclines also causes selection for pathogenicity factors, that is, disease-causing factors. These factors and drug resistance have been shown to be linked on the same plasmid. Pathogenicity and antibiotic resistance can therefore be transferred simultaneously to other organisms. 

Mammalian cells (and some bacteria) lack the enzymes required for folate synthesis from PABA and depend on exogenous sources of folate therefore, they are not susceptible to sulfonamides. Sulfonamide resistance may occur as a result of mutations that (1) cause overproduction of PABA, (2) cause production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides, or (3) impair permeability to the sulfonamide. Dihydropteroate synthase with low sulfonamide affinity is often encoded on a plasmid that is transmissible and can disseminate rapidly and widely. Sulfonamide-resistant dihydropteroate synthase mutants also can emerge under selective pressure. 

Correct answer = C. Trimethoprim is 20 to 50 times more potent than sulfamethoxazole. It inhibits the enzyme dihydrofolate reductase, thus preventing both purine and pyrimidine synthesis. Trimethoprim resistance has been observed in gram-negative bacteria caused by the presence of a plasmid that codes for an altered dihydrofolate reductase with a lower affinity for the drug. 

Resistance can be caused by 1) decreased uptake of drug when the oxygen-dependent transport system for aminoglycosides is absent an altered receptor where the 30S ribosomal subunit binding site has a lowered affinity for aminoglycosides plasmid-associated synthesis of enzymes (for example, acetyltransferases, nucleotidyltransferases, and phosphotransferases) that modify and inactivate aminoglycoside... 

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. 

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