Mechanisms and evolution of colistin resistance in clinical Enterobacteriaceae

Abstract

Escherichia coli and Klebsiella pneumoniae as multidrug-resistant Gram-negative opportunistic pathogens Escherichia coli and Klebsiella pneumoniae are facultative anaerobic, rod-shaped, Gram-negative opportunistic pathogens in the Enterobacteriaceae family, and are asymptomatic colonizers of the intestinal microbiota (1-3). In addition, K. pneumoniae also asymptotically colonizes the skin, and the upper respiratory tract. E. coli and K. pneumoniae are frequently observed pathogens, that can cause infections outside of their respective niches. Common opportunistic infections caused by both E. coli and K. pneumoniae are bloodstream, and urinary tract infections (4-7). Individually, E. coli is well known to cause enteric infections (1, 5), whilst K. pneumoniae may also cause soft tissue infections, and pneumonia (2, 8). K. pneumoniae, together with Enterococcus faecium, Staphylococcus aureus, Acinetobacter baumannii, Pseudomonas aeruginosa, and species from the Enterobacter genus, is a member of the group of ESKAPE pathogens (9). Together, like the acronym of their genus names suggests, they are known for their ability to evade the effects of antibiotic treatments in patients, through various mechanisms of antibiotic resistance. Due to the increasing rate of antibiotic resistance, it has been suggested to include E. coli in this group; forming the ESKAPEE pathogens (10). Colistin is the type of polymyxin in which the variable groups are: l-Dab at position 3, d-leucine at position 6, l-leucine at position 7, and l-threonine at position 10 respectively (Figure 1B) (32, 35). Colistin comes in two different forms, in which the fatty acid group varies between (S)-6-methyloctanoyl (polymyxin E1, or colistin A), and 6-methylheptanoyl (polymyxin E2, or colistin B) (32, 35). Commercial preparations of colistin consists of a mixture of both colistin A and colistin B (36). Although these forms differ in their fatty acid group, differences in their bactericidal activity are negligible (37). Colistin is selectively bactericidal for Gram-negative aerobic bacilli, and does not affect Gram-positive bacteria, and acid-fast bacteria. Colistin is only active against Gram-negative bacteria because of the presence of LPS molecules in the membranes of this type of bacteria (32, 38-40). Some specific Gram-negative aerobic bacilli are however, intrinsically resistant to colistin. These species include: