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The antimicrobial resistance crisis is a global health issue requiring discovery and development of novel therapeutics. However, conventional screening of natural products or synthetic chemical libraries is uncertain. Combination therapy using approved antibiotics with inhibitors targeting innate resistance mechanisms provides an alternative strategy to develop potent therapeutics. This review discusses the chemical structures of effective β-lactamase inhibitors, outer membrane permeabilizers, and efflux pump inhibitors that act as adjuvant molecules of classical antibiotics. Rational design of the chemical structures of adjuvants will provide methods to impart or restore efficacy to classical antibiotics for inherently antibiotic-resistant bacteria. As many bacteria have multiple resistance pathways, adjuvant molecules simultaneously targeting multiple pathways are promising approaches to combat multi-drug-resistant bacterial infections. Ministry of Education (MOE) Submitted/Accepted version This work was funded and supported by the Singapore MOE Tier 3 grant (MOE2018-T3-1-003).

Frequent outbreaks of Salmonella Typhimurium infection in both the animal and human population with potential for zoonotic transmission pose a significant threat to the public health sector. The rapid emergence and spread of more invasive multidrug-resistant clinical isolates of Salmonella further highlight the need for the development of new drugs with effective broad-spectrum bactericidal activities. Synthesis and evaluation of main-chain cationic polyimidazolium 1 (PIM1) against several gram-positive and gram-negative bacteria have previously demonstrated the efficacy profile of PIM1. The present study focuses on antibacterial and anti-biofilm activities of PIM1 against Salmonella both in vitro and in ovo setting. In vitro, PIM1 exhibited bactericidal activity against all tested three strains of Salmonella at a low dosage of 8 μg/ml. Anti-biofilm activity of PIM1 was evident with complete inhibition for the initial attachment of biofilms at 16 μg/ml and degradation of pre-formed biofilms in a dose-dependent manner. During the host cell infection process, PIM1 reduces extracellular bacterial adhesion and invasion rates to limit the establishment of infection. Once intracellular, the drug-resistant strain was tolerant and protected from PIM1 treatment. In a chicken egg infection model, PIM1 exhibited therapeutic activity for both Salmonella strains with stationary-phase and exponential-phase inocula. Moreover, PIM1 showed a remarkable efficacy against the stationary phase inocula of drug-resistant Salmonella by eliminating the bacteria burden in >50% of infected chicken egg embryos. Collectively, PIM1 has demonstrated its potential as a drug candidate for treatment of Salmonella infections, as well as a solution to tackle egg contamination issues on poultry farms.

In recent years, infectious diseases have again become a critical threat to global public health largely due to the challenges posed by antimicrobial resistance. Conventional antibiotics have played a crucial role in combating bacterial infections; however, their efficacy is significantly impaired by widespread drug resistance. Natural antimicrobial peptides (AMPs) and their polymeric mimics demonstrate great potential for killing bacteria with low propensity of resistance as they target the microbial membrane rather than a specific molecular target, but they are also toxic to the host eukaryotic cells. To minimize antibiotics systemic spread and the required dose that promote resistance and to advocate practical realization of the promising activity of AMPs and polymers, smart systems to target bacteria are highly sought after. This review presents bacterial recognition by various specific targeting molecules and the delivery systems of active components in supramolecules. Bacteria-induced activations of antimicrobial-based nanoformulations are also included. Recent advances in the bacteria targeting and delivery of synthetic antimicrobial agents may assist in developing new classes of highly selective antimicrobial systems which can improve bactericidal efficacy and greatly minimize the spread of bacterial resistance.

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.

The rapid emergence and spread of drug-resistant bacteria, as one of the most pressing public health threats, are declining our arsenal of available antimicrobial drugs. Advanced antimicrobial drug delivery systems that can achieve precise and controlled release of antimicrobial agents in the microenvironment of bacterial infections will retard the development of antimicrobial resistance. A variety of extracellular enzymes are secreted by bacteria to destroy physical integrity of tissue during their invasion of host body, which can be utilized as stimuli to trigger "on-demand" release of antimicrobials. In the past decade, such bacterial enzyme responsive drug release systems have been intensively studied but few review has been released. Herein, we systematically summarize the recent progress of smart antimicrobial drug delivery systems triggered by bacteria secreted enzymes such as lipase, hyaluronidase, protease and antibiotic degrading enzymes. The perspectives and existing key issues of this field will also be discussed to fuel the innovative research and translational application in the future.

Carbapenem‐resistant Gram‐negative bacteria (GNB) are heading the list of pathogens for which antibiotics are the most critically needed. Many antibiotics are either unable to penetrate the outer‐membrane or are excluded by efflux mechanisms. Here, we report a cationic block β‐peptide (PAS8‐b‐PDM12) that reverses intrinsic antibiotic resistance in GNB by two distinct mechanisms of action. PAS8‐b‐PDM12 does not only compromise the integrity of the bacterial outer‐membrane, it also deactivates efflux pump systems by dissipating the transmembrane electrochemical potential. As a result, PAS8‐b‐PDM12 sensitizes carbapenem‐ and colistin‐resistant GNB to multiple antibiotics in vitro and in vivo. The β‐peptide allows the perfect alternation of cationic versus hydrophobic side chains, representing a significant improvement over previous antimicrobial α‐peptides sensitizing agents. Together, our results indicate that it is technically possible for a single adjuvant to reverse innate antibiotic resistance in all pathogenic GNB of the ESKAPE group, including those resistant to last resort antibiotics. Accepted version

Correction for ‘Polymers as advanced antibacterial and antibiofilm agents for direct and combination therapies’ by Zhangyong Si et al., Chem. Sci., 2022, 13, 345–364, https://doi.org/10.1039/D1SC05835E.

The growing prevalence of antimicrobial drug resistance in pathogenic bacteria is a critical threat to global health. Conventional antibiotics still play a crucial role in treating bacterial infections, but the emergence and spread of antibiotic-resistant micro-organisms are rapidly eroding their usefulness. Cationic polymers, which target bacterial membranes, are thought to be the last frontier in antibacterial development. This class of molecules possesses several advantages including a low propensity for emergence of resistance and rapid bactericidal effect. This review surveys the structure–activity of advanced antimicrobial cationic polymers, including poly(α-amino acids), β-peptides, polycarbonates, star polymers and main-chain cationic polymers, with low toxicity and high selectivity to potentially become useful for real applications. Their uses as potentiating adjuvants to overcome bacterial membrane-related resistance mechanisms and as antibiofilm agents are also covered. The review is intended to provide valuable information for design and development of cationic polymers as antimicrobial and antibiofilm agents for translational applications., This review surveys the structure–activity of advanced antimicrobial cationic polymers with low toxicity and high selectivity. Their uses as potentiating adjuvants and as antibiofilm agents are also covered.

We report the first demonstration of the efficient bacteria targeting properties of DNA-based polymeric micelles with high-density DNA corona. Nanoscale polymer micelles derived from DNA-b-polystyrene (DNA-b-PS) efficiently selected most tested Gram-positive strains over Gram-negative strains; single-strand DNAs were 20-fold less selective. We demonstrate that these targeting properties were derived from the interaction between densely packed DNA strands of the micelle corona and the peptidoglycan layers of Gram-positive bacteria. DNA-b-PS micelles incorporating magnetic nanoparticles (MNPs) can efficiently capture and concentrate Gram-positive bacteria suggesting the simple applications of these DNA block copolymer micelles for concentrating bacteria. Adenine (A), thymine (T), cytosine (C), and guanine (G)-rich nanostructures were fabricated, respectively, for investigating the effect of sequence on Gram-selective bacteria targeting. T-rich micelles showed the most efficient targeting properties. The targeting properties of these DNA nanostructures toward Gram-positive bacteria may have applications as a targeted therapeutic delivery system. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Nanyang Technological University Accepted version This work was funded and supported by an ASTAR RIE2020 Advanced Manufacturing and Engineering (AME) IAP-PP Specialty Chemicals Programme (SERC Grant No. A1786a0032), the Singapore MOE Tier 3 grant (MOE2018-T3-1-003) and the NTU NAFTEC funding. Zhangyong Si and Jianghua Li acknowledge the support of NTU through an NTU Research scholarship. Zhang Kaixi acknowledges the support of NTU through an Interdisciplinary Graduate School (IGS) (HealthTech) PhD scholarship.

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.

Zwitterionic polymers are classical antifouling polymers but they require specialized monomers that have cationic and anionic charges integrated into a single monomer. Herein, we show that pseudo-zwitterionic copolymers synthesized from a mixture of 2 monomers each having a single opposite polarity has excellent antibiofilm efficacy. We have discovered a new mixed-charge copolymer brush (#1-A) synthesized from 2 oppositely charged monomers, the anionic SPM (3-Sulfopropyl methacrylate) and the cationic AMPTMA ((3-Acrylamidopropyl) trimethylammonium chloride), that achieves broad spectrum in vitro antibiofilm effect of greater than 99% reductions against all six Gram-positive and Gram-negative bacteria tested. In the murine subcutaneous wound catheter infection models, the #1-A has good long-term anti-biofilm efficacy against MRSA and Pseudomonas aeruginosa of 3.41 and 3.19 orders respectively, outperforming previous mixed-charge copolymer coatings. We discovered a new method to choose the cationic/anionic pair combination to form the best antibiofilm copolymer brush coating by exploiting the solution polymerization kinetics disparity between the cationic and anionic monomers. We also showed that #1-A is softer and has higher hydration than the classical zwitterionic polymer. This study shows the possibility of achieving potent antibiofilm efficacy by combining readily available opposite singly charged monomers. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Ministry of Health (MOH) Nanyang Technological University Accepted version This research is supported by the Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 3 grants (MOE2013-T3-1-004 and MOE2018-T3-1-003). The authors also thank the funding support from a Singapore Ministry of Health Industry Alignment Fund (NMRC/MOHIAFCAT2/003/2014), an A*STAR Industry Alignment Fund (Wound Care Innovation for the Tropics IAF-PP (HBMS Domain), H17/01/a0/0M9), an A*STAR RIE2020 Advanced Manufacturing and Engineering (AME) IAP-PP Specialty Chemicals Program (Grant No. A1786a0032) and Nanyang Technological University (NTU).

The treatment of bacterial infections is hindered by the presence of biofilms and metabolically inactive persisters. Here, we report the synthesis of an enantiomeric block co-beta-peptide, poly(amido-D-glucose)-block-poly(beta-L-lysine), with high yield and purity by one-shot one-pot anionic-ring opening (co)polymerization. The co-beta-peptide is bactericidal against methicillin-resistant Staphylococcus aureus (MRSA), including replicating, biofilm and persister bacterial cells, and also disperses biofilm biomass. It is active towards community-acquired and hospital-associated MRSA strains which are resistant to multiple drugs including vancomycin and daptomycin. Its antibacterial activity is superior to that of vancomycin in MRSA mouse and human ex vivo skin infection models, with no acute in vivo toxicity in repeated dosing in mice at above therapeutic levels. The copolymer displays bacteria-activated surfactant-like properties, resulting from contact with the bacterial envelope. Our results indicate that this class of non-toxic molecule, effective against different bacterial sub-populations, has promising potential for the treatment of S. aureus infections., The authors report the synthesis of an enantiomeric block co-beta-peptide that kills methicillin-resistant Staphylococcus aureus, including biofilm and persister bacterial cells, and disperses biofilms. The copolymer displays antibacterial activity in human ex vivo and mouse in vivo infection models without toxicity.

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

In this work, the iron-mediated (dual) concurrent ATRP–RAFT polymerization of water-soluble poly(ethylene glycol) monomethyl ether methacrylate (PEGMA) was investigated at different polymerization temperatures (from 90 °C to 30 °C), using 2-cyanoprop-2-yl-1-dithionaphthalate (CPDN) as an alkyl pseudohalide initiator, ethyl 2-bromoisobutyrate (EBiB) as a co-initiator, and FeCl3·6H2O/PPh3 complex as the catalyst. The polymerization kinetics was studied in detail at polymerization temperatures of 90 °C and 30 °C. The results showed that the concurrent ATRP–RAFT polymerization (using only CPDN as the initiator) of PEGMA could be carried out successfully, even if the polymerization temperature was reduced to 30 °C. Furthermore, the polymerization rate was remarkably enhanced via dual concurrent ATRP–RAFT polymerization (using CPDN and EBiB as co-initiators). For example, the monomer conversion could be higher than 70% in the dual concurrent ATRP–RAFT polymerization system in 65.5 h, while a conversion of only 22% could be obtained after 167 h for the concurrent ATRP–RAFT polymerization system at 30 °C. The “living” features of dual concurrent ATRP–RAFT polymerization of PEGMA were verified by chain end analysis and chain-extension experiments.