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New antimicrobials are urgently needed to combat Gram-negative bacteria, particularly multi-drug resistant (MDR) and phenotypically resistant biofilm species. At present, only sequence-defined alpha-peptides (e.g. polymyxin B) can selectively target Gram-negative bacterial lipopolysaccharides. We show that a copolymer, without a defined sequence, shows good potency against MDR Gram-negative bacteria including its biofilm form. The tapered blocky co-beta-peptide with controlled N-terminal hydrophobicity (#4) has strong interaction with the Gram-negative bacterial lipopolysaccharides via its backbone through electrostatic and hydrogen bonding interactions but not the Gram-positive bacterial and mammalian cell membranes so that this copolymer is non-toxic to these two latter cell types. The new #4 co-beta-peptide selectively kills Gram-negative bacteria with low cytotoxicity both in vitro and in a mouse biofilm wound infection model. This strategy provides a new concept for the design of Gram-negative selective antimicrobial peptidomimetics against MDR and biofilm species. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Submitted/Accepted version This research is supported by the Ministry of Education, Singapore, under its MOE AcRF Tier 3 Awards of MOE2018-T3-1-003 and MOE2013-T3-1-002. Zhangyong Si acknowledges the support of an NTU Ph.D. scholarship. The authors thank the NSCC and ASTAR ACRC for providing the computational resources to perform simulations and A*STAR for support (grant IDs H17/01/a0/010, IAF111213C). We also thank the A*STAR Wound Care Innovation for the Tropics IAF-PP (HBMS Domain) with grant number H17/01/a0/0M9, the A*STAR RIE2020 Advanced Manufacturing and Engineering (AME) IAP-PP Specialty Chemicals Programme (Grant No. A1786a0032) and A*STAR Career Development Award (CDA, Grant No. 202D8155), the Major Project of 2025 Sci &Tech Innovation of Ningbo, China (2018B10052) and NTU for funding support.

Cationic polymers are promising antibacterial agents since they have a low propensity for bacteria to evolve resistance, but they usually have low biocompatibility due to their hydrophobic moieties. Herein, we report a new biodegradable and biocompatible chitosan-derived cationic antibacterial polymer, 2,6-Diamino Chitosan (2,6-DAC). 2,6-DAC shows excellent broad-spectrum antimicrobial activity with minimum inhibitory concentrations (MICs) of 8-32 µg/mL against clinically relevant and multi-drug resistant (MDR) bacteria including Listeria monocytogenes, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. Further, 2,6-DAC shows an excellent synergistic effect with various clinically relevant antibiotics proved by decreasing the MICs of the antibiotics against MDR A. baumannii and MRSA to 2.4 log10 reduction of A. baumannii in murine intraperitoneal and lung infection models. The novel chitosan derivative, 2,6-DAC, can be utilized as biocompatible broad-spectrum cationic antimicrobial agent alone or in synergistic combination with various antibiotics. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Ministry of Health (MOH) Nanyang Technological University Accepted version We thank the funding support from Singapore Ministry of Education Tier 3 grants (MOE2013-T3-1-002, MOE2018-T3-1-003), a Singapore Ministry of Health Industry Alignment Fund (NMRC/ MOHIAFCAT2/003/2014) and NTU. We also thank the ASTAR Wound Care Innovation for the Tropics IAF-PP (HBMS Domain) with grant number H17/01/a0/0M9, and ASTAR RIE2020 Advanced Manufacturing and Engineering (AME) IAP-PP Specialty Chemicals Programme (Grant No. A1786a0032). We also thank the Major Project of 2025 Sci&Tech Innovation of Ningbo (2018B10052) and NSF of China, 8147179.

Antimicrobial peptides that target the integrity of bacterial envelopes can eradicate pathogens with little development of resistance, but they often inflict nonselective toxicity toward mammalian cells. The prevailing approach to optimize the selectivity of cationic peptides has been to modify their composition. Instead, we invent a new generation of broad-spectrum antibacterial nanoconstructs with negligible mammalian cell toxicity through a competitive displacement of counter polyanions from the complementary polycations. The nanoconstruct, which has a highly cationic Au nanoparticles (NPs) core shielded by polymeric counterions, is inert in nonbacterial environments. When exposed to negatively charged bacterial envelopes, this construct sheds its polyanions, triggering a cationic Au NP/bacterial membrane interaction that rapidly kills Gram-positive and Gram-negative bacteria. The anionic charge and hydrophilicity of the polyanion provides charge neutralization for the peptide-decorated Au NP core, but it is also bacteria-displaceable. These results provide a foundation for the development of other cationic particles and polymeric counterion combinations with potent antimicrobial activity without toxicity. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Nanyang Technological University Accepted version This work was funded and supported by the Singapore Ministry of Education Tier 3 Grants (MOE2013-T3-1-002 and MOE2018-T3-1-003), ASTAR RIE2020 Advanced Manufacturing and Engineering (AME) IAP-PP Specialty Chemicals Programme Grant (No. A1786a0032), and NTU NAFTEC Funding.

Medical device contamination caused by microbial pathogens such as bacteria and fungi has posed a severe threat to the patients’ health in hospitals. Due to the increasing resistance of pathogens to antibiotics, the efficacy of traditional antibiotics treatment is gradually decreasing for the infection treatment. Therefore, it is urgent to develop new antibacterial drugs to meet clinical or civilian needs. Antibacterial polymers have attracted the interests of researchers due to their unique bactericidal mechanism and excellent antibacterial effect. This article reviews the mechanism and advantages of antimicrobial polymers and the consideration for their translation. Their applications and advances in medical device surface coating were also reviewed. The information will provide a valuable reference to design and develop antibacterial devices that are resistant to pathogenic infections. Ministry of Education (MOE) Published version The authors acknowledge the financial supports from Major Project of 2025 Sci&Tech Innovation (2018B10052) of Ningbo, China, and the Singapore Ministry of Education Tier 3 grant (MOE2018-T3-1-003). This work was also sponsored by K.C. Wang Magna/Education Fund of Ningbo University.

The development of novel reagents and antibiotics for combating multidrug resistance bacteria has received significant attention in recent years. In this study, new antimicrobial star polymers (14–26 nm in diameter) that consist of mixtures of polylysine and glycopolymer arms were developed and were shown to possess antimicrobial efficacy toward Gram positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) (with MIC values as low as 16 μg mL–1) while being non-hemolytic (HC50 > 10 000 μg mL–1) and exhibit excellent mammalian cell biocompatibility. Structure function analysis indicated that the antimicrobial activity and mammalian cell biocompatibility of the star nanoparticles could be optimized by modifying the molar ratio of polylysine to glycopolymers arms. The technology described herein thus represents an innovative approach that could be used to fight deadly infectious diseases. NMRC (Natl Medical Research Council, S’pore) Accepted version