The PagP protein mediates the palmytoylation of lipid A, a structural modification associated with bacterial resistance to alpha-helical antimicrobial peptides (AMPs) such as cecropin (Pontes et al. 2011).
Lee, H., Hsu, F. F., Turk, J. & Groisman, E. A. The PmrA-regulated pmrC gene mediates phosphoethanolamine modification of lipid A and polymyxin resistance in Salmonella enterica.
In the article by Qureshi et al [ 10], phosphoethanolamine modifications of lipid A were present among all colistin-resistant A. baumannii isolates.
Interestingly, the modifications of lipid A that are associated with polymyxin resistance may negatively affect the virulence potential, a topic currently under debate [ 91, 92].
Therefore, inhibitors of the Ara4N Lipid A modification pathway would not only enhance the ability of the host immune system to clear the infection but could also be administered together with clinically useful CAMPs such as polymyxins to increase their effectiveness.
The bacterial cell is able to reduce the initial electrostatic attraction by reducing net negative charge of OM via lipid A modification, thereby increasing resistance to polymyxin.
Since low energy CID does not always provide sufficient fragmentation, other MS/MS strategies have been explored as well as MS n methods which provide both genealogical insight about consecutive fragmentation pathways as well as hierarchical information useful for deeper characterization of lipid A structures and modifications.
Recently, it has been shown that even in E. coli PmrD can link the PhoP/Q and BasS/R two-component systems upon depletion of Mg2+ and promote lipid A modification by inducting the transcription of eptA and arnT genes [ 63].
Conservation of genes related to enterohemolysin and lipid A modification suggests they are part of the EHEC core virulence factors (Additional file 1: Figure S9).
We propose that ArnB is an excellent target for development of selective inhibitors that would abolish lipid A modification and render bacteria sensitive to host CAMPs and antibiotics that act by similar mechanisms such as Colistin.
