Whether resistance is intrinsic or acquired, bacteria share similar pathways or strategies to effect resistance to antimicrobial agents. Of the pathways listed in Figure 1, those that involve enzymatic destruction or alteration of the antibiotic, decreased intracellular uptake or accumulation of drug, and altered antibiotic target are the most common. One or more of these pathways may be expressed by a single cell successfully avoiding and protecting itself from the action of one or more antibiotics.

Fig1. Overview of common pathways bacteria use to effect  antimicrobial resistance. 

Resistance to Beta-Lactam Antibiotics

As discussed earlier, bacterial resistance to beta-lactams may be mediated by enzymatic destruction of the antibiotics (β-lactamase); altered antibiotic targets, resulting in low affinity or decreased binding of antibiotic to the target PBPs; or decreased intracellular uptake or increased cellular efflux of the drug (Table 1). All three pathways play an important role in clinically relevant antibacterial resistance, but bacterial destruction of β-lactams through the production of β-lactamases is by far the most common method of resistance. Extended spectrum β-lactamases are derived from β-lactamases and confer resistance to both penicillins and cephalosporins; carbapenemases are active against carbapenem drugs, such as imipenem. β-lactamases open the drug’s β-lactam ring, and the altered structure prevents subsequent effective binding to PBPs; consequently, cell wall synthesis is able to continue (Figure 2).

Table1. Summary of Resistance Mechanisms for Beta-Lactams, Vancomycin, Aminoglycosides, and Fluoroquinolones

Fig2. Mode of β-lactamase enzyme activity. The enzyme  cleaves the β-lactam ring, and the molecule can no longer bind to  penicillin-binding proteins (PBPs) and is no longer able to inhibit cell  wall synthesis. (Modified from Salyers AA, Whitt DD, editors: Bacterial pathogenesis: a molecular approach, Washington, DC, 1994,  ASM Press.)

Staphylococci are the gram-positive bacteria that most commonly produce beta-lactamase; approximately 90% or more of clinical isolates are resistant to penicillin as a result of enzyme production. Rare isolates of enterococci also produce β-lactamase. Gram-negative bacteria, including Enterobacteriaceae, P. aeruginosa, and Acinetobacter spp., produce dozens of different β-lactamase types that mediate resistance to one or more of the β-lactam antibiotics.

Although the basic mechanism for β-lactamase activity shown in Figure 2 is the same for all types of these enzymes, there are distinct differences. For example, β-lactamases produced by gram-positive bacteria, such as staphylococci, are excreted into the surrounding environment, where the hydrolysis of β-lactams takes place before the drug can bind to PBPs in the cell membrane (Figure 3). In contrast, β-lactamases produced by gram-negative bacteria remain intracellular, in the peri plasmic space, where they are strategically positioned to hydrolyze beta-lactams as they traverse the outer mem brane through water-filled, protein-lined porin channels (see Figure 3). β-lactamases also vary in their spectrum of substrates; that is, not all β-lactams are susceptible to hydrolysis by every β-lactamase. For example, staphylococcal β-lactamase can readily hydrolyze penicillin and penicillin derivatives (e.g., ampicillin, mezlocillin, and piperacillin); however, it cannot effectively hydrolyze many cephalosporins or imipenem.

Fig3. Diagrammatic summary of β-lactam resistance mechanisms for gram-positive and gram-negative bacteria. A, Among gram positive bacteria, resistance is mediated by β-lactamase production and altered PBP targets. B, In gram-negative bacteria, resistance can  also be mediated by decreased uptake through the outer membrane porins. 

Various molecular alterations in the β-lactam structure have been developed to protect the β-lactam ring against enzymatic hydrolysis. This development has resulted in the production of more effective antibiotics in this class. For example, methicillin and the closely related agents oxacillin and nafcillin are molecular derivatives of penicillin that by the nature of their structure are not susceptible to staphylococcal β-lactamases. These agents are the mainstay of antistaphylococcal therapy. Similar strategies have been applied to develop penicillins and cephalosporins that are more resistant to the variety of β-lactamases produced by gram-negative bacilli. Even with this strategy, it is important to note that among common gram-negative bacilli (e.g., Enterobacteriaceae, P. aeruginosa, and Acinetobacter spp.), the list of molecular types and numbers of β-lactamases continues to emerge and diverge, thus challenging the effectiveness of currently available β-lactam agents.

Another therapeutic strategy has been to combine two different β-lactam moieties. One of the β-lactams (the β-lactamase inhibitor) has little or no antibacterial activity but avidly and irreversibly binds to the β-lactamase, rendering the enzyme incapable of hydrolysis; the second β-lactam, which is susceptible to β-lactamase activity, exerts its antibacterial activity. Examples of β-lactam/ β-lactamase inhibitor combinations include ampicillin/ sulbactam, amoxicillin/clavulanic acid, and piperacillin/ tazobactam.

Altered targets also play a key role in clinically relevant β-lactam resistance (see Table 1). Through this pathway the organism changes, or acquires from another organism, genes that encode altered cell wall synthesizing enzymes (i.e., PBPs). These “new” PBPs continue their function even in the presence of a β-lactam antibiotic, usually because the beta-lactam lacks sufficient affinity for the altered PBP. This is the mechanism by which staphylococci are resistant to methicillin and all other β-lactams (e.g., cephalosporins and imipenem). Methicillin-resistant S. aureus produces an altered PBP called PBP2a. PBP2a is encoded by the gene mecA. Because of the decreased binding between β-lactam agents and PBP2a, cell wall synthesis proceeds. Therefore, strains exhibiting this mechanism of resistance must be challenged with a non–β-lactam agent, such as vancomycin, another cell wall–active agent. Changes in PBPs are also responsible for ampicillin resistance in Enterococcus faecium and in the widespread β-lactam resistance observed in S. pneumoniae and viridans streptococci.

Because gram-positive bacteria do not have outer membranes through which β-lactams must pass before reaching their PBP targets, decreased uptake is not a pathway for β-lactam resistance among these bacteria. However, diminished uptake can contribute significantly to β-lactam resistance seen in gram-negative bacteria (see Figure 3). Changes in the number or characteristics of the outer membrane porins through which β-lactams pass contribute to absolute resistance (e.g., P. aeruginosa resistance to imipenem). Additionally, porin changes combined with the presence of certain β-lactamases in the periplasmic space may result in clinically relevant levels of resistance.

Resistance to Glycopeptides

 To date, acquired, high-level resistance to vancomycin has been commonly encountered among enterococci, rarely among staphylococci, and not at all among streptococci. The mechanism involves the production of altered cell wall precursors unable to bind vancomycin with sufficient avidity to allow inhibition of peptidoglycan synthesizing enzymes. The altered targets are readily incorporated into the cell wall, allowing synthesis to progress (see Table 1). A second mechanism of resistance to glycopeptides, described only among staphylococci to date, results in a lower level of resistance; this mechanism is thought to be mediated by overproduction of the peptidoglycan layer, resulting in excessive binding of the glycopeptide molecule and diminished ability of the drug to exert its antibacterial effect.

Because enterococci have high-level vancomycin resistance genes and also the ability to exchange genetic information, the potential for spread of vancomycin resistance to other gram-positive genera poses a serious threat to public health. In fact, the emergence of vancomycin-resistant S. aureus clinical isolates has been documented. In all instances the patients were previously infected or colonized with enterococci. Resistance to vancomycin by enzymatic modification or destruction has not been described.

Resistance to Aminoglycosides

Analogous to beta-lactam resistance, aminoglycoside resistance is accomplished by enzymatic, altered target, or decreased uptake pathways (see Table 1). Gram positive and gram-negative bacteria produce several different aminoglycoside-modifying enzymes. Three general types of enzymes catalyze one of the following modifications of an aminoglycoside molecule:

• Phosphorylation of hydroxyl groups

• Adenylation of hydroxyl groups

• Acetylation of amine groups

Once an aminoglycoside has been modified, its affinity for binding to the 30S ribosomal subunit may be sufficiently diminished or totally lost, allowing protein synthesis to occur.

Aminoglycosides enter the gram-negative cell by passing through outer membrane porin channels. Therefore, porin alterations may also contribute to aminoglycoside resistance among these bacteria. Although some mutations that resulted in altered ribosomal targets have been described, this mechanism of resistance is rare in bacteria exposed to commonly used aminoglycosides.

Resistance to Quinolones

 Enzymatic degradation or alteration of quinolones has not been fully described as a key pathway for resistance. Resistance is most frequently mediated either by a decrease in uptake or in accumulation or by production of an altered target (see Table 1). Components of the gram-negative cellular envelope can limit quinolone access to the cell’s interior location where DNA processing occurs. Other bacteria, notably staphylococci, exhibit a mechanism by which the drug is “pumped” out of the cell, thus keeping the intracellular quinolone concentration sufficiently low to allow DNA processing to continue relatively unaffected. This “efflux” process, therefore, is a pathway of diminished accumulation of drug rather than of diminished uptake.

The primary quinolone resistance pathway involves mutational changes in the targeted subunits of the DNA gyrase. With a sufficient number or substantial major changes in molecular structure, the gyrase no longer binds quinolones, so DNA processing is able to continue.

Resistance to Other Antimicrobial Agents

 Bacterial resistance mechanisms for other antimicrobial agents involve modifications or derivations of the recur ring pathway strategies of enzymatic activity, altered target, or decreased uptake (Box 1).

Box1. Bacterial Resistance Mechanisms  for Miscellaneous Antimicrobial Agents

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مواضيع ذات صلة

Antimicrobial Chemoprophylaxis

Drug–Pathogen Relationships

Measurement of Antimicrobial Activity

Clinical Implications of Drug Resistance

Origin of drug resistance

Resistance to Sulfonamide

Control of Antibiotics Overuse

International Distribution of Antibiotics: A Scandinavian Example

Rediscovery of Penicillin by a Basic Scientific Approach

Penicillin: the First Antibiotic

Sulfonamide: the First Antibacterial Agent Acting Selectively

Drug elimination