Mechanisms of resistance to antibiotics

Mechanisms of resistance to antibiotics amongst strains of Ps. aeruginosa can be divided into two broad groups (i) intrinsic resistance, the type of mechanism often invoked when no obvious resistance mechanism is involved and (ii) enzymatic resistance, leading to chemical modification and subsequent inactivation of the antibiotic. 

G.D. Wright, Mechanisms of resistance to antibiotics, Curr. Opin. Chem. Biol. 2003, 7,1-7. 

Bryan L.E General mechanisms of resistance to antibiotics. J. Antimicrobial Chemotherapy 22 (suppl. 

Biochemical mechanism of resistance to aminoglycosidic antibiotics, H. Umezawa, Adv. Carbohydr. Chem. Biochem., 30 (1974) 183-225. 

The following sections describe the biochemical mechanisms of resistance to different classes of antibiotics, with the antibiotics grouped according to their mechanism of action. 

Three mechanisms of resistance to the aminoglycoside-aminocyclitol (AGAC) group of antibiotics are recognized (Shaw et al. 1993). 

Abstract Resistance to modern antibiotics is currently a major health concern in treating infectious diseases. Abuse, overuse, and misuse of antibiotics in treating human illness have caused the pathogens to develop resistance through a process known as natural selection. The most common mechanism of resistance to -lactam antibiotics is the production of /3-lactamases, which destroy -lactam antibiotics before they reach the bacterial target. Over the last two decades, combination therapy involving treatment with a -lactam antibiotic and a /3-lactamase inhibitor has become very successful in controlling -lactamase-mediated bacterial resistance. Currently available inhibitors like... 

J. M. Frere, B. Joris, B. Granier, A. Matagne, F. Jacob, C. Bourguignon-Bellefroid, Diversity of the Mechanisms of Resistance to beta-Lactam Antibiotics , Res. Microbiol. 1991, 142, 705-710. 

The second mechanism of resistance to beta-lactam antibiotics can appear as a change in target PBP, which is expressed in a reduction in the affinity to beta-lactam molecules. 

Finally, the most important mechanism of resistance to beta-lactam antibiotics is the production of beta-lactamase by the bacteria. Beta-lactamases break the C-N bond in the beta-lactam ring of antibiotics. Since its existence is absolutely necessary for reacting with PBP, a break in the beta-lactam ring leads to a loss of antibacterial activity. 

It is clinically important to understand the nature of the mechanism of resistance to an antibiotic drug. For example, the -lactam resistance of Streptococcus pneumoniae is due to the appearance of altered penicillinbinding proteins. Thus, the use of a combination of a 3-lactam and a penicillinase inhibitor, such as clavulanate, wUl not overcome streptococcal -lactam resistance, because the mechanism of resistance is not due to the production of a penicillinase. 

B. Humans cannot synthesize folic acid (A) diet is their main source. Sulfonamides selectively inhibit microbially synthesized folic acid. Incorporation (B) of PABA into microbial folic acid is competitively inhibited by sulfonamides. The TMP-SMX combination is synergistic because it acts at different steps in microbial folic acid synthesis. All sulfonamides are bacteriostatic. Inhibition of the transpeptidation reaction (C) involved in the synthesis of the bacterial cell wall is the basic mechanism of action of (3-lac-tam antibiotics Changes in DNA gyrases (D) and active efflux transport system are mechanisms for resistance to quinolones. Structural changes (E) in dihydropteroate synthetase and overproduction of PABA are mechanisms of resistance to the sulfonamides. 

Mechanisms of Resistance. Three distinct biochemical mechanisms of resistance to tetracyclines have been identified. The energy-dependent efflux of antibiotic mediated by resistance proteins located in the bacterial... 

These mechanisms are of considerable microbiological and biochemical interest, although not all of the above agents find current use as biocides. The plasmid-mediated efflux pumps are particularly important, since efflux is one means whereby acquired resistance to antibiotics occurs (see earlier) and can be a mechanism of resistance to some clinically useful biocides (see later). No efflux pump comparable to those described for arsenate and cadmium [212] has yet been detected in silver-resistant bacteria [213] however, an up-to-date assessment of this subject is available [212]. 

Beta-lactamases are genetically and strnctnraUy closely related to peniciUin-bmding proteins. Their prodnction by bacteria is a major mechanism of resistance to the action of beta-lactam antibiotics. Dmgs have therefore been developed that inhibit beta-lactamase, as a way of overcoming this resistance (SEDA-20,229). They are beta-lactam compounds with particularly high affinities for beta-lactamases (1,2), which therefore act as competitive inhibitors of beta-lactamases. Beta-lactamase inhibitors have no important antimicrobial activity and are only given in combination with an antimicrobial beta-lactam. 

Two new mechanisms of resistance to P-lactams have been reviewed. The "tolerant" S, aureus strains are Inhibited by low penicillin concentrations, but not by high concentrations, probably due to an excess of an inhibitor of autolysln. Enz3nne preparations, derived from Infected, human inflammatory exudate, were found to inactivate several 3-lactams but not other types of antibiotics. ... 

Answer E. For antitubercular activity, isoniazid (INH) must first be metabolically activated via a catalase present in mycobacteria. A decrease in expression of the cat G gene that encodes this enzyme is the mechanism of high-level resistance to INH. Low-level resistance occurs via mutations in the inh A gene that codes for an enzyme involved in synthesis of mycolic acids. Mutations in the gene that codes for DNA-dependent RNA polymerase is an important mechanism of resistance to rifampin and related antibiotics. 

In this chapter, the molecular-biological mode of action of macrolide antibiotics and the biochemical and genetic mechanisms of resistance to MLS antibiotics are reviewed. Based on a recent X-ray crystallographic study on a 50S ribosomal subunit from Haloarcula marismortui and the finding of intracellular macrolide accumulation, the mode of action from the viewpoint of a new hypothetical concept, deposition binding, and mechanisms of drug resistance in clinically isolated bacteria are discussed. In addition, recent major developments in macrolide antibiotics are briefly described. 

The molecular biological mode of action of macrolide antibiotics and the biochemical and genetic mechanism of resistance to macrolide, lincosamide, and type B streptogramin antibiotics were reviewed in this chapter. 

Matsuoka, M., Endou, K., Saitoh, S., Katoh, M., and Nakajima, Y. (1995). A mechanism of resistance to partial macrolide and streptogramin B antibiotics in Staphylococcus aureus clinically isolated in Hungary. Biol. Pharm Bull. 18, 1482-1486. 

Studies on biochemical mechanisms of resistance to aminoglycoside antibiotics have revealed that they are enzymically inactivated in several... 

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