How do bacterial membranes resist polymyxin antibiotics?

Abstract

In our recent Communications Biology article, we reported on the biophysical mechanism of resistance for polymyxin antibiotics in bacterial membranes. The emergence of plasmid-borne colistin resistance poses a threat to our last line of defense against many pathogens. Here, we outline the current understanding of mcr-1-mediated polymyxin resistance, and propose future directions for membrane-targeting antibiotic research. Polymyxin antibiotics, such as colistin, have important roles in both medicine and agriculture. However, the use of polymyxins for the latter endangered its use in the former. The first transmissible plasmid-bearing resistance to colistin was reported by Liu and colleagues in 2016, and isolates of Escherichia coli harboring this resistance have been found in livestock across southeastern Asia 1. Expression of the resistance gene, mcr-1, causes modification of lipid A in the bacterial outer surface, resulting in reduced affinity for polymyxins. Worryingly, the gene can be readily passed between different bacterial strains making widespread polymyxin resistance inevitable 2. Wang and colleagues reported on the global distribution of mcr-1 and showed the resistance gene is currently present across five continents, as shown in Fig. 1 (ref. 3). Polymyxin antibiotics kill bacteria by damaging their cell membranes, but now bacteria have figured out how to inhibit this process. Biophysical tools, such as diffraction and molecular dynamics computer simulations, have provided important insights into these mechanisms 4,5. In order to prolong the lifespan of current polymyxins and develop new ones, it is critical to gain a detailed understanding of the biophysics of polymyxin-bacteria interactions. How do polymyxins damage bacterial membranes? The earliest high-resolution studies showed that polymyxins can kill bacteria by puncturing holes into their outer surface, and causing leakage of internal contents 6-8. Polymyxin B and colistin are both cationic antimicrobial peptides that are attracted to the net anionic bacterial outer membrane, resulting in an electrostatic attraction between drug and target. The polymyxin creates local curvature in the membrane, while the membrane itself repels the insertion process. At a critical point, the hydrophobic tail of the polymyxin can insert into the bacterial membrane and create a lipid defect by separating lipids away from one another. When fully inserted into the

A novel chemical biology and computational approach to expedite the discovery of new-generation polymyxins against life-threatening Acinetobacter baumannii

“… 17 The asymmetricity and heterogeneity of our lipidomics-informed OM model well represents the complexity of the bacterial OM 18,19 and allowed us to precisely determine membrane–polymyxin interactions at the membrane level. 12 Furthermore, we synthesized a series of polymyxin B 3 (PMB 3 ) analogs with alanine-substitution at each amino acid position except the bridging Dab 4 (Fig. S2–S12, ESI † ).…”

“…Our ndings reveal that modications of the lipid A phosphate groups substantially minimize their interaction with polymyxins. 12,13 Additionally, the fatty acyl chain, D-Phe 6 and Leu 7 made hydrophobic contacts with the tails of lipid A. Energy analysis revealed electrostatic interactions from Dab 1 (À51.6 AE 2.9 kcal mol À1 ) and Dab 9 (À96.5 AE 8.1 kcal mol À1 ) made prominent contributions to OM binding, which is $5-10 fold greater than the hydrophobic interactions from D-Phe 6 (À12.6 AE 0.4 kcal mol À1 ), the fatty acyl group (À10.9 AE 0.5 kcal mol À1 ), and Leu 7 (À10.4 AE 0.2 kcal mol À1 ) (Fig.…”

“…However, these simplified LPS-based SAR models fail to mimic polymyxin interactions with the bacterial OM, thereby hampering our understanding of their exact mode of action. 12 Here, we employed an experimentally-based bacterial OM model rather than a single LPS molecule to develop a novel polymyxin SAR model through integrating all-atom molecular dynamics (MD) simulations and chemical biology approaches. Our in vitro results supported the utility of this SAR model to predict the antimicrobial activity of polymyxin analogs, which will significantly accelerate the discovery of next-generation polymyxins against problematic Gram-negative pathogens.…”

Hyaluronan/Diethylaminoethyl Chitosan Polyelectrolyte Complexes as Carriers for Improved Colistin Delivery

“…The proposed modification of CT release from polymeric PEC compared to the release profile of free CT will allow targeted drug delivery to the sites of bacterial inflammation due to the high affinity of HA for the relevant receptors (CD44, stabilin-2, and TLR4 [33][34][35][36][37][38][39][40]. However, the initial rapid CT release is also necessary to ensure high antibiotic doses in the first hours after administration, since the bactericidal effect of CT is mainly realized via the carpet model of insertion, and it is dose-dependent [42][43][44][45].…”

Polymyxin Delivery Systems: Recent Advances and Challenges

“…For this reason, bacterial resistance to polymyxins is relatively rare compared to resistance to other antibiotics. Therefore, polymyxins are currently the last-line antibiotic for multidrug-resistant Gram-negative infections [46][47][48][49][50][51][52]. Polymyxin resistance is mainly caused by structural remodeling of lipid A, located on the bacterial cell surface, via biochemical and genetic mechanisms.…”