Membrane permeabilization of colistin toward pan-drug resistant Gram-negative isolates

Abstract

Pan-drug resistant Gram-negative bacteria, being resistant to most available antibiotics, represent a huge threat to the medical community. Colistin is considered the last therapeutic option for patients in hospital settings. Thus, we were concerned in this study to demonstrate the membrane permeabilizing activity of colistin focusing on investigating its efficiency toward those pan-drug resistant isolates which represent a critical situation. We determined the killing dynamics of colistin against pan-drug resistant isolates. The permeability alteration was confirmed by different techniques as: leakage, electron microscopy and construction of an artificial membrane model; liposomes. Moreover, selectivity of colistin against microbial cells was also elucidated. Colistin was proved to be rapid bactericidal against pan-drug resistant isolates. It interacts with the outer bacterial membrane leading to deformation of its outline, pore formation, leakage of internal contents, cell lysis and finally death. Furthermore, variations in membrane composition of eukaryotic and microbial cells provide a key for colistin selectivity toward bacterial cells. Colistin selectively alters membrane permeability of pan-drug resistant isolates which leads to cell lysis. Colistin was proved to be an efficient last line treatment for pan-drug resistant infections which are hard to treat.

Development and Challenges of Antimicrobial Peptides for Therapeutic Applications

“…Oritavancin and telavancin may either form membrane pores or channels, or lyse the membrane. Colistin forms pore-like aggregates in the bacterial cell membrane and disrupts the membrane; thus, it results in lytic cell death [66,67].…”

“…These peptides bind to cell membranes and spontaneously assemble in the lipid bilayer as a channel or pore-like structure, though not all are cytolytic ( Figure 5). Well-known natural examples are gramicidin [68], colistin [67], melittin [69,70], maculatin [71], and alamethicin [72]. The two common models for the channel structures are barrel-stave and toroidal, depending on how the peptide interacts with the lipid headgroups [73].…”

“…The pore size, which varies among different peptides, can be measured by several biophysical techniques and molecular dynamics simulations [44,71,[74][75][76][77]. Membrane-lytic peptides, e.g., daptomycin [23,24,26,78,79], colistin [67], LL-37 [80], aurein 1.2 [81,82], and piscidin 1 [83,84], disrupt cell membranes, like detergents. These peptides accumulate on the membrane surface, carpet the membrane at a critical threshold concentration, and destabilize and permeabilize the membrane structure.…”

Trends, Epidemiology, and Management of Multi-Drug Resistant Gram-Negative Bacterial Infections in the Hospitalized Setting

“…The mechanism through which it works is electrostatic destabilization of the outer membrane of Gram-negative bacteria. Colistin disrupts the divalent bonds within LPS structures, leading to the leaked contents of the bacterial cell and subsequent cell death [31]. It is generally used in combination with carbapenems such as meropenem to combat resistance, though monotherapy for patients with low risk BSI is acceptable [21].…”

“…As of 2016, only 64.2% of hospitals across the U.S. have met all criteria. The goal is to get to 100% by 2020 [31,60]. In 2016, the Healthcare Infection Control Practices Advisory Committee (HICPAC) released recommendations to further guide the implementation of ASPs.…”