Macromolecular-clustered facial amphiphilic antimicrobials

Md Anisur Rahman,Edgar Luat,Mitzi Nagarkatti,Moumita Sharmin Jui,Marpe Bam,Alan W Decho,Tinom Shokfai,Chuanbing Tang,Mitra S Ganewatta

doi:10.1038/s41467-018-07651-7

Md Anisur Rahman, Edgar Luat + Show 7 more

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https://doi.org/10.1038/s41467-018-07651-7

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Bacterial infections and antibiotic resistance, particularly by Gram-negative pathogens, have become a global healthcare crisis. We report the design of a class of cationic antimicrobial polymers that cluster local facial amphiphilicity from repeating units to enhance interactions with bacterial membranes without requiring a globally conformational arrangement associated with highly unfavorable entropic loss. This concept of macromolecular architectures is demonstrated with a series of multicyclic natural product-based cationic polymers. We have shown that cholic acid derivatives with three charged head groups are more potent and selective than lithocholic and deoxycholic counterparts, particularly against Gram-negative bacteria. This is ascribed to the formation of true facial amphiphilicity with hydrophilic ion groups oriented on one face and hydrophobic multicyclic hydrocarbon structures on the opposite face. Such local facial amphiphilicity is clustered via a flexible macromolecular backbone in a concerted way when in contact with bacterial membranes.

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Bacterial infections and antibiotic resistance, by Gram-negative pathogens, have become a global healthcare crisis
Each monomer of MAECA, MAEDA, and MAELA was polymerized via reversible addition-fragmentation chain transfer (RAFT) polymerization utilizing 4-cyano-4-(thiobenzylthio)pentanoic acid as a chain transfer agent
Our results demonstrated that the higher charge densities of a polymer could lead to more significant interactions with bacterial membranes, similar to observations made by Yang and colleagues[46,47]

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Bacterial infections and antibiotic resistance, by Gram-negative pathogens, have become a global healthcare crisis. The clinical applications of AMPs are very limited due to their low bioavailability, low stability, high manufacturing cost, as well as in many cases nonspecific toxicity to mammalian cells[7,13,19,24] To address these issues, synthetic polymers with cationic charges, which mimic natural AMPs and selectively attack negative bacterial cell membranes over zwitterionic mammalian cell membranes, have been studied widely as a promising solution to combat bacteria. Gellman and coworkers stated that the facial amphiphilicity could be achieved from random copolymerization of hydrophobic and hydrophilic monomers that did not require control of subunit sequences[16,36,37] Their copolymers contained both cationic and lipophilic groups as well as sufficiently flexible backbones that could form a globally amphiphilic, but conformationally irregular helical structure induced by negatively charged bacterial membranes (Fig. 1b). From the perspective of free energy change upon the contact with bacterial cell membranes, the fact of adopting a facial amphiphilic conformation without the helical structures from random coil structures of synthetic polymers would suffer a very high entropic penalty from a whole macromolecule (Fig. 1b)

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