Loss of the Bordetella bronchiseptica O-polysaccharide, which is negatively charged because of the presence of uronic acid, rendered mutant
strains highly susceptible to various AMPs (Banemann et al., 1998). As for CPS and exopolysaccharide, O-polysaccharide has been proposed to act as a protective shield preventing AMPs from interacting with the bacterial membrane. Similarly, S. Typhimurium mutants lacking the O-polysaccharide were more susceptible to polymyxin B (Nagy et al., 2006; Ilg et al., 2009). In contrast, loss of the B. cenocepacia O-polysaccharide did not result in higher sensitivity to polymyxin B (Loutet et al., 2006), suggesting Hormones antagonist some heterogeneity in shielding effects between bacterial species. Polysaccharides appear to not be the only bacterial surface structures able to trap AMPs. In a recent study, curli fimbriae
expressed by UPEC were shown to bind LL-37 and increase resistance to this AMP (Kai-Larsen et al., 2010). Binding of LL-37 to both monomeric and polymeric CsgA, the major curli subunit, might be due to the overall negative charge of CsgA at physiological pH. In Gram-negative bacteria, the lipid A and core moieties of lipopolysaccharide can be covalently modified either within the OM or during Selleckchem CYC202 lipopolysaccharide synthesis and transport to the OM. Lipopolysaccharide modifications are often regulated by environmental stimuli through two-component signaling systems. They promote virulence, modulate the TLR4-mediated inflammatory response, and confer resistance to AMPs (Miller et al., 2005). Lipopolysaccharide modifications, especially those of the lipid A moiety, were shown to largely impact bacterial resistance to AMPs by reinforcing
the OM permeability barrier and neutralizing the negative charges of lipopolysaccharide thereby preventing AMP binding (Fig. 1c). Although lipopolysaccharide modifications have been most extensively studied in S. Typhimurium, their importance PAK6 in conferring resistance to AMPs is also evident for many Gram-negative pathogens including Yersinia spp., E. coli, P. aeruginosa, and Neisseria spp. (Richards et al., 2010). PagP is an OM enzyme that transfers a palmitoyl group from phospholipids to lipid A, resulting in a hepta-acylated lipid A. In S. Typhimurium, this modification was shown to reinforce the OM permeability barrier and increase resistance to the AMPs C18G and protegrin (Guo et al., 1998). Interestingly, PagP remains dormant in the OM, and it becomes activated upon OM disruption leading to perturbation in the lipid asymmetry (Jia et al., 2004). Disruption of the OM by self-uptake of AMPs is therefore likely to be one of the signals stimulating PagP activity. Other lipopolysaccharide modifications occur at the periplasmic side of the OM prior to lipopolysaccharide transport to the OM. The arnBCADTEF operon (also known as pmrHFIJKLM operon) is responsible for the biosynthesis and transfer of L-Ara4N to the 4′phosphate of lipid A.