Mechanisms of Bacterial Antibiotic Resistance

The mechanisms of resistance have developed in response to the mechanisms of action of antimicrobial drugs. Antimicrobial agents are generally categorized according to their targeted sites of action. To date, three classes of antibiotic resistance have been described intrinsic resistance, acquired resistance, and genetic resistance (Hancock, 1998). 2.4.1 Intrinsic resistance: This includes outer membrane impermeability, efflux pumps, and enzymes. 2.4.1.1 Outer membrane impermeability: The outer membrane constitutes a semi-permeable barrier to the uptake of antibiotics and substrate molecules. Because uptake of small hydrophilic molecules such as β-lactams is restricted to a small portion of the outer membrane (namely the water filled channels of porin proteins), the outer membrane limits the movement of such molecules into the cell (Bellido et al., 1992). Compared with Gram-positive cells, Gram-negative bacteria are
covered with one additional membrane layer, the outer membrane (OM). It was thus hypothesized that the OM would serve as a general permeability barrier that the slows down the diffusion of various types of solutes, including drugs, and that this would contribute to the intrinsic drug resistance that find in Gram-negative bacteria (Nikaido and Vaara, 1985). It was recognized early in the history of antibiotic development that penicillin is effective against Gram-positive bacteria but not against Gram-negative ones. The difference in susceptibility to pencillin is due in large part to the outer membrane, a lipid bilayer that acts as a barrier to the penetration of antibiotics into the cell (Nikaido, 1985). 2.4.1.2 Efflux pumps: By a change in membrane permeability that makes the drug unable to penetrate through the membrane into the cell. This may be due to a change in structural protein, a decrease in pore size or an alteration in the transport system. Alternatively the rate of efflux of the drug from the cell may be increased making the drug unable to attain a sufficiently high concentration inside the cell to cause inhibition. This is the basic of resistance to tetracyclines (Delgadillo et al., 1993). An efflux system, involving three proteins (Mex A, Mex B, and Opr M) is critical for the intrinsic resistance of P. aeruginosa. Mutation in any of the genes encoding these proteins led to a fourfold to tenfold increase in susceptibility to quinolones, β-lactams (except imipenem), tetracycline, and chloramphanicol (Poole et al., 1993). Promotion of antibiotic efflux: In some strains of S. pneumoniae, S. aureus, Strept. pyogenes and S. epidermidis, an active efflux mechanism causes resistance to macrolides, streptogramins and azalides (Sutcliffe et al., 1996). Active efflux mechanisms may also contribute to the full expression of β-lactam resistance in Pseudomonas aeruginosa (Stikumar and Poolek, 1997). 2.4.1.3 Enzymes: Resistance due to Enzymic Inactivation: Two types of enzymes inactivate penicillins and cephalosporins. These are the acylases (amidases), which split the peptide bond linking the side chains to the 6-aminopenicillanic acid or 7-aminocephalosporanic acid nucleus, and the β-lactamases, which hydrolyse the CO__N bond of the β-lactam ring (Figure 1). Acylases are produced by a wide range of bacteria and moulds Hamilton-Miller, (1966). Since 6-amino penicillanic acid, the product of the reaction, has a low antibacterial activity against most micro-organisms, it has been suggested that the ability to produce acylases may contribute to the resistance of an organism to penicillin. However, the amount of enzyme produced is small and the conditions required for maximal activity are unlikely to obtain in vivo Cole and Sutherland, (1966). It seems, therefore, that these enzymes are unimportant factors in penicillin resistance. The acylases are of great value in breaking down natural penicillins to yield the penicillin nucleus from which the semi-synthetic penicillins are derived (Batchelor et al. 1961). The β-Lactamases: β-lactam antibiotics are antibacterial agents that share the structure feature of a β-lactam ring are known to be very diverse (Greenwood, 1995). Resistance to β-lactam antibiotics is due mainly to the production of β-lactamases, enzymes that inactivates these antibiotics by splitting the amide bond of the β-lactam ring. Numerous β-lactamases exist, encoded either by chromosomal genes or by transferable genes located on plasmids or transposons (Medeiros, 1984). These enzymes new first detected by Abraham and Chain, (1940) in extracts of penicillin-resistant strains of E. Coli and other Gram-negative bacteria, and have since been demonstrated in penicillin- or cephalosporin-resistant strains of most bacterial species. One of the first-recognized ways for bacteria to resist the actions of antimicrobial agents was the production of enzymes that inactivate a drug. Aminoglycosides and chloramphenicol have been found to be affected by inactivating enzymes, but the classic example of this phenomenon is β-lactamase production. Since their introduction into clinical practice, the effectiveness of β-lactam antibiotics has been reduced by the occurrence of bacteria that are resistant to their mode of action. Resistant Staphylococcus aureus strains were reported very soon after the introduction of benzyl penicillin into clinical practice (Abraham and Chain, 1940). Other than the intrinsic resistance resulting from insusceptible targets or inadequate penetration of the drug through the Gram-negative outer membrane, resistance to this class of antibiotic is most frequently due to the production of β-lactamase enzymes that hydrolyze the β-lactam bond in these antibiotics, thus destroying their functionality (Livermore, 1995). need to know more read www.amazon.com/Manual-Antibiotics-Mechanisms-Resistance