Efflux systems antibiotic resistance

Bacterial resistance can be caused by actively pumping antibiotics out of the cell and therefore decreasing the concentration at the target site. Drug efflux systems in bacteria are classified into four major groups based on their sequence homologies and functional similarities (Table 3). 

An alternative to most of these mechanisms is the existence of efficient efflux systems, so that toxic concentrations of the drug are not achieved. There are three major families of proton-dependent multidrug efflux systems (1) the major facilitator superfamily, (2) the small multidrug resistance family, and (3) the resistance/nodulation/cell division family (Paulsen et al. 1996). It should be emphasized that several of these systems are involved not with antibiotic efflux but with, for example, acriflavine, chlorhexidine, and crystal violet. An attempt is made only to outline a few salient features of the resistance/nodulation/cell division family that mediates antibiotic efflux, and these are given in Table 3.3 (Nikaido 1996). They consist of a transporter, a linker, and an outer membrane channel. 

Aminoglycoside efflux is a significant mechanism of aminoglycoside resistance in bacteria of the genera Pseudomonas, Burkholderia, and Stenotrophomonas. There are five classes of transmembrane efflux systems associated with antibiotic resistance however, the resistance nodulation division (RND) family is the predominant class (Table 3.1). ... 

B. Overproduction (A) of PABA is one of the resistance mechanisms of sulfonamides. Changes in the synthesis of DNA gyrases (B) is a well-described mechanism for quinolone resistance. Plasmid-mediated resistance (C) does not occur with quinolones. An active efflux system for transport of drug out of the cell has been described for quinolone resistance, but it is not plasmid mediated. Inhibition of structural blocks (D) in bacterial cell wall synthesis is a basic mechanism of action of p-lactam antibiotics. Inhibition of folic acid synthesis (E) by blocking different steps is the basic mechanism of action of sulfonamides. 

Table 2 Selected antibiotic resistance efflux systems...

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. 

Plasmid-mediated resistance to tetracyclines is widespread. Tetracycline-resistant organisms show decreased intracellular accumulation of the drugs. Resistance mechanisms include decreased activity of the uptake systems and the development of mechanisms (efflux pumps) for active extrusion of tetracyclines. Plasmids that include genes involved in the production of efflux pumps for tetracyclines commonly include resistance genes for multiple antibiotics. 

The targets of antibiotics and the different resistance mechanisms present in bacteria have been summarized by Coates and Henderson. Antibiotics mainly focus on the disturbance of the synthesis of DNA, the cell wall, the cell membrane, and proteins. Resistant bacteria are equipped with certain defense mechanisms, e.g. they decrease the uptake of antibiotics, use highly effective efflux pumps for active transport of the drugs out of the cells, they alter the target size of enzymes or they use enzymes which alter and degrade the antibiotics themselves (Figure 15.1). These different defense systems force the human civilization to continuously establish new, efficient drugs with new modes of action, otherwise humanity will end up in a pre-antibiotic area. ... 

The discovery of a global regulatory system for virulence in S. aureus, mediated by small auto-inducing peptides (AlPs) has opened a new avenue to the interruption of microbial defences, and consequently, to overcoming resistance to many antibiotics. Microbial defensive mechanisms, based on mutation, drug efflux pathways, biofilm formation and the secretion of virulence factors, have become the major threat to modem antibiotic therapy. 

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