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Cationic Lignin-Based Hyperbranched Polymers to Circumvent Drug Resistance in Pseudomonas Keratitis

The rise of antimicrobial-resistant bacteria strains has been a global public health concern due to their ability to cause increased patient morbidity and a greater burden on the healthcare system. As one of the potential solutions to overcome such bacterial infections, hyperbranched copolymers with cationic charges were developed. These copolymers were assessed for their antimicrobial efficacy and their bactericidal mechanisms. They were found to be potent against mobile colistin-resistant 1 strains, which was significant as colistin is known to be the last-resort antibiotic against Gram-negative bacteria. Furthermore, there was no sign of mutational resistance developed by E. ColiATCC 25922 and MCR 1+E. Coli against the copolymer even up to 20 passages. The ability to evade inducing resistance would provide invaluable insights for future antibiotic development. Their studies suggest that the bactericidal efficacy comes from the ability to target the outer membrane efficaciously. In vivo study using a Pseudomonas keratitis model showed that the copolymer was compatible with the eye and further supported that the copolymer treatment was effective for complete bacteria elimination.

Infections caused by microorganisms have raised concerns regarding their effects on global public health. Although many bacterial infections can be treated successfully with the right antibiotics, the excessive use of such antibiotics has resulted in the rapid emergence of antibiotic-resistant strains in recent years.(1) Such microbes include methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis, vancomycin-resistant enterococci, ampicillin-resistant Escherichia coli, and vancomycin-resistant S. aureus.These strong microbes increase both patient morbidity as well as the burden on the healthcare systems. The antimicrobial pipeline is dominated by modification of existing antibiotics, which do not avert the evolution of antimicrobial resistance completely. Therefore, this issue calls for the development of a new class of antimicrobial agents.

1H NMR spectra of cationic lignin-based hyperbranched polymers (LD50, A,B) and the quaternized lignin copolymer by benzyl bromide (C: partially quaternized and D: fully quaternized).

Synthetic polymers are a new generation of antimicrobial agents.With unique amphiphilic structures, these cationic materials are able to disintegrate bacterial membranes and cause cell death by selectively binding to negatively charged phosphate head groups on the membranes. Compared to the antibiotic resistance developed from rapid gene mutation, synthetic antimicrobial polymers are less likely to be met with bacterial resistance as it would be difficult for bacteria to generate an evolutionary composition of their entire membrane. However, while synthetic polymers show advantages such as a low manufacturing cost, good stability, and potential for multiple applications, they exhibit poor biocompatibility and biodegradability.

Lignin is the richest biopolymer of aromatics that is readily available from the cell wall of wood and annual plants. More than 50 million tons of lignin are generated annually as byproducts from the pulp and paper industry, but about 98% of them are treated as waste and used in low-value applications.The valorization of lignin could potentially solve the issue of rapidly depleting fossil fuels and also improve the economic viability of these biomasses.

Slit-lamp biomicroscopy and AS-OCT images showing the progression of P. aeruginosa infection in the scarified cornea before and after treatment with (A) PBS copolymer, (B) pBLD50, and (C) gatifloxacin. (D) Average CT determined from AS-OCT images after treatment with various groups. *, p < 0.05 vs PBS by Dunnett’s multiple comparison test. BL indicates baseline CT. (E) Bacterial bioburden in the cornea after treatment with various groups. **, p < 0.01 by the Mann–Whitney test.

Moreover, lignin itself exhibits many attractive properties, including biodegradability, antioxidant activity, and antimicrobial properties. Early studies have looked at the potential of using lignin as an antimicrobial agent, but the killing mechanism and the efficacy of the materials systems need further investigation. The inherent antibacterial properties of lignin stem from the phenolic components, especially those with a double bond in α, β-positions and a methyl group in the γ-position. The antimicrobial efficacy of lignin is highly dependent on its origin and extraction method.This causes some degree of variability in the efficacy of the materials.

Representative slit-lamp and AS-OCT images showing the progression of P. aeruginosa keratitis in PBS-treated eyes. Note the presence of substantial haze and conjunctival chemosis at 24 h post infection (p.i.).

In this study, they developed a series of cationic lignin-based hyperbranched polymers and investigated their antimicrobial activities. Extensive studies were carried out to understand their antimicrobial performance against existing antibiotics, and eventually, a copolymer was selected for in vivo evaluation against P. aeruginosa keratitis in a rabbit model. P. aeruginosa is the causative agent for a wide range of infections. Extensive contact lens use typically results in this bacterial contamination leading to bacterial keratitis. Clinical outcomes of corneal infections with P. aeruginosa are often poor. Treatment with antibiotics is often long and costly and could lead to the progressive mutation to drug-resistant bacteria. This thus poses a need for effective antimicrobial alternatives, such as the developed copolymers.

Cationic Lignin-Based Hyperbranched Polymers to Circumvent Drug Resistance in Pseudomonas Keratitis Pei Lin Chee, Cally Owh, Mayandi Venkatesh, Mercy Halleluyah Periayah, Zheng Zhang, Pek Yin Michelle Yew, Huajun Ruan, Rajamani Lakshminarayanan, Dan Kai, and Xian Jun Loh ACS Biomaterials Science & Engineering Article ASAP DOI: 10.1021/acsbiomaterials.1c00856


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