Chapter 66 : Mechanisms of Resistance to Antibacterial Agents

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Antimicrobial resistance arises by (i) mutation of cellular genes, (ii) acquisition of exogenous resistance genes, or (iii) mutation of acquired genes. The most completely studied example of regulatory mutation resulting in resistance is the derepression of the chromosomal β-lactamase of spp. As bacteria have responded to the challenge of antimicrobial agents, so have researchers responded to the challenge of antibiotic resistance. The majority of pumps that extrude one or more antibiotic classes from the bacterial cell are located in the cytoplasmic membrane and use proton motive force to drive drug efflux. This chapter describes resistance mechanisms for different antimicrbial classes. In explaining resistance to aminoglycosides (amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, streptomycin, and tobramycin), the chapter explains how aminoglycosides reach their target in bacterial cells and then reviews their mechanism of action. The clinical indications for aminoglycoside therapy are also summarized in the chapter. Resistance to aminoglycosides can occur by four mechanisms: (i) loss of cell permeability (decreased uptake), (ii) alterations in the ribosome that prevent binding, (iii) expulsion by efflux pumps, and (iv) enzymatic inactivation by aminoglycoside-modifying enzymes (AMEs). The most common mechanism of resistance to chloramphenicol is the elaboration of CATs. The antibiotics nitrofurazone and nitrofurantoin are used in the treatment of genitourinary infections and as topical antibacterial agents. The ultimate importance of efflux pump activations for clinical resistance to tigecycline awaits more extensive clinical use.

Citation: Rice L, Bonomo R. 2011. Mechanisms of Resistance to Antibacterial Agents, p 1082-1114. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch66
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Image of FIGURE 1

Serine β-lactamases and their reactions with β-lactam carbonyl donors. Modified from reference .

Citation: Rice L, Bonomo R. 2011. Mechanisms of Resistance to Antibacterial Agents, p 1082-1114. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch66
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Image of FIGURE 2

Representation of the crystal structure of the AcrAΒ-TolC three-component RND multidrug efflux pump. On the left are the three components of the pumps as they link the cytoplasmic (inner) membrane to the outer membrane. The periplasmic linker protein (AcrA) is shown only in outline to allow visualization of the linkage between AcrB and TolC. On the right, an outline of the pump shown at the left is presented, detailing the functional regions of the pump. Reprinted with permission from reference 182.

Citation: Rice L, Bonomo R. 2011. Mechanisms of Resistance to Antibacterial Agents, p 1082-1114. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch66
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Image of FIGURE 3

Sites of modification on kanamycin B by various AMEs. The arrows point to the sites of modification by the specific enzymes, namely, acetyltransferases, phosphotransferases, and nucleotidyltransferases. Reprinted with permission from reference 145.

Citation: Rice L, Bonomo R. 2011. Mechanisms of Resistance to Antibacterial Agents, p 1082-1114. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch66
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