Enhanced Synergistic Antibacterial and Antibiofilm Efficacy of Main-Chain Polysulfoniums with Antibiotics by Balancing Charge Density and Amphiphilicity

Abstract

Infection diseases caused by Gram-negative pathogens are exceedingly difficult to treat because their characteristic outer membrane limits antibiotic entry. Herein, we report the development of main-chain polysulfoniums with different charge densities and amphiphilicities based on the quantitative methylation reaction. By regulating the membrane-disruption capability, the combined efficacy of polysulfoniums and antibiotic rifampicin can be manipulated from no interaction to synergy against Gram-negative bacteria Escherichia coli. After incubating with synergistic polysulfoniums/rifampicin combinations at a minimum inhibitory concentration (MIC), the time needed to achieve a 6-log reduction of E. coli can be accelerated 8 times compared to the antibiotic treatment. At 1/2 MIC, polysulfoniums/rifampicin combinations can provide a 90% reduction in biofilm mass and 8-log orders of embedded bacteria killing in 3-day-mature E. coli biofilms. This work demonstrates that alkylation chemistry can serve as a reliable means to create antibiotic adjuvants in combating infections caused by Gram-negative pathogens and biofilms.

Precision Dosing of Antibiotics and Potentiators by Hypoxia-Responsive Nanoparticles for Overcoming Antibiotic Resistance in Gram-Negative Bacteria

“…Following the same synthetic strategy, a multiblock copolymer, azo- alt -PS + 2 , was prepared for comparison, as the PS + 2 building block is known to have a weak interaction with the bacterial membrane (Schemes B and S2). It should be noted that the PTE2 precursor polymer exhibited a molecular weight (4400) and polydispersity (1.38) comparable to those of PTE1 (Figure S4). The complete formation of sulfonium cations, alternating multiblock architecture, and comparable molecular weights of polymers were confirmed by 1 H NMR, UV–vis, and GPC measurements (Figures S3–S5).…”

“…Over recent decades, the pipeline of antibiotics acting against bacteria has been running dry. , As most discovered candidate antibiotics suffer from insufficient potency, pharmacokinetic properties, or toxicity, it is imperative to explore avenues that breathe new life into existing drugs. − This is particularly important for the treatment of infections caused by Gram-negative bacteria. Due to the presence of an outer membrane that acts as an evolving antibiotic barrier, Gram-negative bacteria are intrinsically resistant to many antibiotics. , To tackle this issue, antibacterial cationic polymers have then been explored for use in enhancing the intracellular transportation of ineffective antibiotics by perturbing the outer membrane of Gram-negative bacteria. − The amphiphilic balance and charge density of polycations have been demonstrated as critical factors in regulating the synergistic activity with antibiotics . However, due to the systemic toxicity of polycations and undesired pharmacokinetics of antibiotics in the bloodstream, the clinical application of a combination of antibiotics and cationic potentiators is still impeded.…”

“…12−19 The amphiphilic balance and charge density of polycations have been demonstrated as critical factors in regulating the synergistic activity with antibiotics. 20 However, due to the systemic toxicity of polycations and undesired pharmacokinetics of antibiotics in the bloodstream, the clinical application of a combination of antibiotics and cationic potentiators is still impeded. Overexposure to antibiotics and polycationic might bring a lot of harm to the patient, whereas inadequate antibiotic dosing raises the risk of clinical failure and predisposes the development of antimicrobial resistance.…”

Ammonium, Phosphonium, and Sulfonium Polymers for Antimicrobial Applications: A Comparative Study

“…Quaternary ammonium cations (QACs) in diverse forms ,− are the most commonly used cationic groups in antimicrobial SCPs. , Although QACs were believed to be impervious to resistance, their extensive use as antibacterial agents over the past decades has indeed resulted in the development of drug resistance in certain bacteria. , This has motivated the exploration of other cations for antimicrobial applications. In addition to QACs, phosphonium − and sulfonium − have emerged as two alternative cationic groups for the development of antibacterial polymers. Despite being less investigated, phosphonium- and sulfonium-based polymers have demonstrated considerable potential in complementing polymeric QACs to combat bacterial infections.…”

Broad-Spectrum Antimicrobial Polymer-Coated Fabrics via Commodity Polystyrene Upcycling

“…While this latest pandemic was caused by a virus, infections by pathogenic bacteria and fungi represent no less of a threat due to the emergence of multidrug resistance (MDR). , This critical threat to human health posed by MDR “superbugs” has been attributed to our overuse and misuse of antibiotics and antifungals in past decades. To overcome this problem, functional materials such as antimicrobial peptides, synthetic cationic polymers, − antimicrobial nanomaterials, composites, − and coatings − have been explored. While effective, antimicrobial peptides tend to be costly and susceptible to enzymatic degradation .…”