Antimicrobial nanocomposite coatings for rapid intervention against catheter-associated urinary tract infections.

Catheter-associated urinary tract infections (CAUTIs) pose a significant challenge in hospital settings. Current solutions available on the market involve incorporating antimicrobials and antiseptics into catheters. However, challenges such as uncontrolled release leading to undesirable toxicity, as well as the prevalence of antimicrobial resistance reduce the effectiveness of these solutions. Additionally, conventional antibiotics fail to effectively eradicate entrenched bacteria and metabolically suppressed bacteria present in the biofilm, necessitating the exploration of alternative strategies. Here, we introduce a novel polymer-nanocomposite coating that imparts rapid antimicrobial and anti-biofilm properties to coated urinary catheters. We have coated silicone-based urinary catheters with an organo-soluble antimicrobial polymer nanocomposite (APN), containing hydrophobic quaternized polyethyleneimine and zinc oxide nanoparticles, in a single step coating process. The coated surfaces exhibited rapid eradication of drug-resistant bacteria within 10-15 min, including E. coli, K. pneumoniae, MRSA, and S. epidermidis, as well as drug-resistant C. albicans fungi. APN coated catheters exhibited potent bactericidal activity against uropathogenic strains of E. coli, even when incubated in human urine. Furthermore, the stability of the coating and retention of antimicrobial activity was validated even after multiple washes. More importantly, this coating deterred biofilm formation on the catheter surface, and displayed rapid inactivation of metabolically repressed stationary phase and persister cells. The ability of the coated surfaces to disrupt bacterial membranes and induce the generation of intracellular reactive oxygen species (ROS) was assessed through different techniques, such as electron microscopy imaging, flow cytometry as well as fluorescence spectroscopy and microscopy. The surface coatings were found to be biocompatible in an in vivo mice model. Our simple one-step coating approach for catheters holds significant potential owing to its ability to tackle multidrug resistant bacteria and fungi, and the challenge of biofilm formation. This work brings us one step closer to enhancing patient care and safety in hospitals.

Multifunctional Suture Coating for Combating Surgical Site Infections and Mitigating Associated Complications.

Despite advancements in preventive measures and hospital protocols, surgical site infections (SSIs) remain a significant concern following surgeries. Sutures, commonly used for wound closure, can serve as a platform for microbial adherence and contamination, leading to extensive debridement and recurrent antibiotic therapy. The emergence of drug resistance and the formation of biofilms on sutures have further complicated the management of SSIs. Drug-eluting sutures incorporating biocides like triclosan have limitations due to uncontrolled release and associated toxicity. Therefore, there is a need for alternative approaches to impart antimicrobial properties to sutures. In this study, we present a one-step covalent cross-linking method to coat surgical sutures with an antimicrobial small molecule, quaternary benzophenone-based antimicrobial (QSM). Additionally, the sutures are dip-coated with ibuprofen, a nonsteroidal anti-inflammatory drug with analgesic properties. The coated sutures maintained their morphological and tensile properties after in vivo implantation. The antimicrobial coating demonstrated efficacy against a broad-spectrum pathogens, including drug-resistant bacteria and fungi. The optimized formulation retained its biodegradability in vivo. Furthermore, the coated sutures exhibited ∼3 log reduction in methicillin-resistant Staphylococcus aureus (MRSA) burden in a subcutaneous implantation mouse model. Overall, this multifunctional coating provides antimicrobial properties to surgical sutures while preserving their mechanical integrity and biodegradability. These coated sutures have the potential to address the challenge of SSIs and contribute to improved surgical outcomes.

Versatile and User-Friendly Anti-infective Hydrogel for Effective Wound Healing.

Wound dressings play a crucial role in facilitating optimal wound healing and protecting against microbial infections. However, existing commercial options often fall short in addressing chronic infections due to antibiotic resistance and the limited spectrum of activity against both Gram-positive and Gram-negative bacteria frequently encountered at wound sites. Additionally, complex fabrication processes and cumbersome administration strategies pose challenges for cost-effective wound dressing development. Consequently, there is a pressing need to explore easily engineered biocompatible biomaterials as alternative solutions to combat these challenging wound infections. In this study, we present the development of an anti-infective hydrogel, P-BAC (polymeric bactericidal hydrogel), which exhibits simple administration and promotes efficient wound healing. P-BAC is synthesized via a one-step fabrication method that involves the noncovalent cross-linking of poly(vinyl alcohol), N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride-AgCl nanocomposite, and proline. Remarkably, P-BAC demonstrates broad-spectrum antibacterial activity against both planktonic and stationary cells of clinically isolated Gram-positive and Gram-negative bacteria, resulting in a significant reduction of bacterial load (5-7 log reduction). Moreover, P-BAC exhibits excellent efficacy in eradicating bacterial cells within biofilm matrices (>95% reduction). In vivo experiments reveal that P-BAC accelerates wound healing by stimulating rapid collagen deposition at the wound site and effectively inactivates ∼95% of Pseudomonas aeruginosa cells. Importantly, the shear-thinning property of P-BAC simplifies the administration process, enhancing its practicality and usability. Taken together, our findings demonstrate the potential of this easily administrable hydrogel as a versatile solution for effective wound healing with potent anti-infective properties. The developed hydrogel holds promise for applications in diverse healthcare settings, addressing the critical need for improved wound dressing materials.

Engineering Photo-Crosslinked Antimicrobial Coating to Tackle Catheter-Associated Infections In Vivo.

Microbial colonization on urinary and intravascular catheter surfaces results in steeply rising cases of catheter-associated infections as well as blood stream infections. Currently marketed efforts include impregnation and loading of antimicrobials and antiseptics that leach out into the local environment and inactivate microbes. However, they suffer from uncontrolled release, induction of resistance, and undesired toxicity. Here, in this manuscript, we have developed a photocurable, covalent coating on catheters using quaternary benzophenone-based amide (QSM-1). The coating was found to be active against drug-resistant bacteria and fungi. The coating inactivated stationary and persister cells of superbug MRSA and inhibited the formation of biofilms with retained activity against broad-spectrum bacteria when challenged in realistic urinary conditions. The coating was seen to be biocompatible in vitro and in vivo. Remarkably, the coated catheters showed reduced fouling and >99.9% reduction in bacterial burden when implanted in vivo in a mice model of subcutaneous implantation. We conceive the possibility of application of QSM-1-coated catheters in the healthcare settings to tackle the notorious catheter-associated nosocomial infections.

Permanent, Antimicrobial Coating to Rapidly Kill and Prevent Transmission of Bacteria, Fungi, Influenza, and SARS-CoV-2.

Microbial adhesion and contamination on shared surfaces can lead to life-threatening infections with serious impacts on public health, economy, and clinical practices. The traditional use of chemical disinfectants for sanitization of surfaces, however, comes with its share of health risks, such as hazardous effects on the eyes, skin, and respiratory tract, carcinogenicity, as well as environmental toxicity. To address this, we have developed a nonleaching quaternary small molecule (QSM)-based sprayable coating which can be fabricated on a wide range of surfaces such as nylon, polyethylene, surgical mask, paper, acrylate, and rubber in a one-step, photocuring technique. This contact-active coating killed pathogenic bacteria and fungi including drug-resistant strains of Staphylococcus aureus and Candida albicans within 15-30 min of contact. QSM coatings withstood multiple washes, highlighting their durability. Interestingly, the coated surfaces exhibited rapid killing of pathogens, leading to the prevention of their transmission upon contact. The coating showed membrane disruption of bacterial cells in fluorescence and electron microscopic investigations. Along with bacteria and fungi, QSM-coated surfaces also showed the complete killing of high loads of influenza (H1N1) and SARS-CoV-2 viruses within 30 min of exposure. To our knowledge, this is the first report of a coating for multipurpose materials applied in high-touch public places, hospital equipment, and clinical consumables, rapidly killing drug-resistant bacteria, fungi, influenza virus, and SARS-CoV-2.

Engineering Antimicrobial Polymer Nanocomposites: In Situ Synthesis, Disruption of Polymicrobial Biofilms, and In Vivo Activity.

The increasing incidence of microbial infections and a limited arsenal of effective antibacterial and antifungal agents have entailed the need for new broad-spectrum therapeutics. Polymer-inorganic nanocomposites have emerged as an integral choice of antimicrobials but are limited by complicated synthesis, narrow-spectrum activity, and poor in vivo efficacy. Herein, chloride counterions of a nontoxic, moderately antibacterial polymer have been explored for in situ nanoprecipitation-based synthesis of water-soluble polymer-silver chloride nanocomposites. With the controlled release of silver ions, the nanocomposites were highly active against multidrug-resistant bacteria as well as fluconazole-resistant fungi. Alongside the elimination of metabolically inactive bacterial cells, the nanocomposites disrupted polymicrobial biofilms, unlike antibiotics and only silver-based ointments. This underlined the role of the engineered composite design, where the polymer interacted with the biofilm matrix, facilitating the penetration of nanoparticles to kill microbes. Further, the nanocomposite diminished Pseudomonas aeruginosa burden in mice skin infection (>99.9%) with no dermal toxicity proving its potential for clinical translation.

Polymeric Biomaterials for Prevention and Therapeutic Intervention of Microbial Infections.

The escalating emergence of multidrug-resistant (MDR) pathogens and their ability to colonize into biofilms on a multitude of surfaces have struck global health as a nightmare. The stagnation in the development of antibiotics and the deterioration of clinical pipelines have incited an invigorating search for smart and innovative alternatives in the scientific community. Further, a steep rise in the usage of biomedical devices and implants has resulted in an accelerated occurrence of infections. Toward the goal of mitigation of the aforementioned challenges, antimicrobial polymers have stood out as an astounding option. In this perspective, we highlight our contribution to the field of polymeric biomaterials for tackling antimicrobial resistance (AMR) and infections. Polymers inspired from antimicrobial peptides (AMPs) have been utilized as therapeutic interventions to curb MDR infections and also to rejuvenate obsolete antibiotics. Further, cationic polymers have been used to impart antimicrobial properties to different biomedical surfaces. These cationic polymer-coated surfaces can inactivate pathogens upon contact as well as prevent their biofilm formation. In addition, antimicrobial hydrogels, which are prepared from either inherently antimicrobial polymers or biocide-loaded polymeric hydrogel matrices, have also been engineered. With a brief overview of the progress in the field, detailed elaboration of the polymeric biomaterials for prevention and therapeutic intervention of microbial infections developed by our group is presented. Finally, the challenges in the field of antimicrobial polymers with discussion on the proceedings of polymeric research to alleviate these challenges are discussed.

Advancements in release-active antimicrobial biomaterials: A journey from release to relief.

Escalating medical expenses due to infectious diseases are causing huge socioeconomic pressure on mankind globally. The emergence of antibiotic resistance has further aggravated this problem. Drug-resistant pathogens are also capable of forming thick biofilms on biotic and abiotic surfaces to thrive in a harsh environment. To address these clinical problems, various strategies including antibacterial agent delivering matrices and bactericidal coatings strategies have been developed. In this review, we have discussed various types of polymeric vehicles such as hydrogels, sponges/cryogels, microgels, nanogels, and meshes, which are commonly used to deliver antibiotics, metal nanoparticles, and biocides. Compositions of these polymeric matrices have been elaborately depicted by elucidating their chemical interactions and potential activity have been discussed. On the other hand, various implant/device-surface coating strategies which exploit the release-active mechanism of bacterial killing are discussed in elaboration. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Implantable Materials and Surgical Technologies > Nanomaterials and Implants Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease.

Polymeric paint coated common-touch surfaces that can kill bacteria, fungi and influenza virus.

In the current situation of COVID-19 pandemic, the role of surfaces in transmitting pathogens is clearer than ever. Herein, we report an organo-soluble, quaternary antimicrobial paint (QAP) based on polyethyleneimine (PEI) which was coated on a wide range of surfaces such as polyvinylchloride (PVC), nylon, rubber, aluminum. The coating completely killed drug-resistant bacteria. It showed rapid bactericidal properties with complete killing in 45 min of exposure and lowered bacterial adherence, asserting self-sterilizing nature. The coating exhibited complete killing of stationary phase cells of bacteria. The coating killed drug-resistant C. albicans strains. Importantly, QAP coating showed complete killing of influenza virus (H1N1).

Quaternary Lipophilic Chitosan and Gelatin Cross-Linked Antibacterial Hydrogel Effectively Kills Multidrug-Resistant Bacteria with Minimal Toxicity toward Mammalian Cells.

Wounds or tissue openings in the skin are susceptible to bacterial attack, which can deteriorate and slow down the healing process. In this regard, antimicrobial gels are valuable as they mitigate the infection spread and assist in the healing. Despite the success, commercially available release-active antimicrobial gels suffer from narrow-spectrum activity, resistance induction, reservoir exhaustion, and in some cases may be associated with toxicity. To circumvent these limitations, herein, we have developed new quaternary lipophilic chitosan derivatives (QuaChi) synthesized by modifying the primary alcohol of the sugar moieties without altering the free amino groups of glucosamines. Compared to protonated chitosan, the synthesized derivatives exhibited improved water solubility and enhanced antibacterial activity against multidrug-resistant Gram-positive and Gram-negative bacteria including clinical isolates. The enhanced antibacterial activity was evident from the bacterial membrane depolarization leading to rapid inactivation of ∼105-106 bacterial cells within 2 h. The applicability of the chitosan derivatives was further demonstrated by developing antibacterial hydrogels by cross-linking the free amino groups of QuaChi with biocompatible gelatin through amide linkages. The hydrogel showed ∼5-7 log reduction of various multidrug-resistant bacteria including the stationary-phase cells within 6 h. Scanning electron microscopy revealed the loss of integrity of the bacterial structure when treated with the hydrogel, whereas mammalian cells (human embryonic kidney-293 (HEK-293)), when exposed to the hydrogel, appeared to be healthy with retained morphology. Collectively, these findings suggest that the developed hydrogel formulation can find potential applications to combat notorious drug-resistant bacterial infections in the healthcare settings.

One-Step Curable, Covalently Immobilized Coating for Clinically Relevant Surfaces That Can Kill Bacteria, Fungi, and Influenza Virus.

Microbial attachment and subsequent colonization onto surfaces lead to the spread of deadly community-acquired and hospital-acquired (nosocomial) infections. Cationic polymeric coatings have gained enormous attention to tackle this scenario. However, non-biodegradable cationic polymer coated surfaces suffer from accumulation of microbial debris leading to toxicity and consequent complexities. Synthetic reproducibility and sophisticated coating techniques further limit their application. In this present study, we have developed one-step curable, covalent coatings based on two organo- and water-soluble small molecules, quaternary benzophenone-based ester and quaternary benzophenone-based amide, which can cross-link on surfaces upon UV irradiation. Upon contact, the coating completely killed bacteria and fungi in vitro including drug-resistant pathogens methicillin-resistant Staphylococcus aureus (MRSA) and fluconazole-resistant Candida albicans spp. The coating also showed antiviral activity against notorious influenza virus with 100% killing. The coated surfaces also killed stationary-phase cells of MRSA, which cannot be eradicated by traditional antibiotics. Upon hydrolysis, the surfaces switched to an antifouling state displaying significant reduction in bacterial adherence. To the best of our knowledge, this is the first report of an antimicrobial coating which could kill all of bacteria, fungi, and influenza virus. Taken together, the antimicrobial coating reported herein holds great promise to be developed for further application in healthcare settings.

Charge-Switchable Polymeric Coating Kills Bacteria and Prevents Biofilm Formation in Vivo.

Preventing bacterial biofilm formation on medical devices and implants in vivo still remains a daunting task. Current antibacterial coatings to combat implant-associated infections are generally composed of toxic metals or nondegradable polymers and involve multistep surface modifications. Here, we present a charge-switchable antibacterial and antibiofilm coating based on water-insoluble cationic hydrophobic polymers that are soluble in organic solvents and can be noncovalently coated onto different surfaces. Toward this, a library of quaternary polyethylenimine (QPEI) polymers with an amide or ester group in their pendant alkyl chain was developed. These QPEIs are shown to hydrolyze from active cationic to nontoxic zwitterionic polymers under acidic or enzymatic conditions. Notably, polymers with both zwitterionic and cationic groups, obtained upon partial hydrolysis of QPEIs, are shown to retain their antibacterial activity with much lower toxicity toward mammalian cells. Furthermore, the zwitterionic polymer, a fully hydrolyzed product of the QPEIs, is shown to be nontoxic to mammalian cells in vitro as well as in vivo. The QPEIs, when coated onto surfaces, kill bacteria and prevent formation of biofilms. In an in vivo mice model, the QPEI-coated medical grade catheter is shown to reduce methicillin-resistant Staphylococcus aureus contamination both on the catheter surface and in the adjacent tissues (99.99% reduction compared to a noncoated catheter). Additionally, biofilm formation is inhibited on the catheter surface with negligible inflammation in the adjacent tissue. The above results thus highlight the importance of these polymers to be used as effective antibacterial coatings in biomedical applications.

Amino-Acid-Conjugated Polymer-Rifampicin Combination: Effective at Tackling Drug-Resistant Gram-Negative Clinical Isolates.

Rapid emergence of multidrug-resistant Gram-negative pathogens coupled with their biofilm-forming capability have set a clinical ultimatum to global public health with an increasing rate of mortality. Recently, the World Health Organization (WHO) identified Acinetobacter baumannii, Pseudomonas aeruginosa, and enterobacteriaceae (Klebsiella pneumoniae, E. coli, etc.) as the pathogens of top priority because of their ability to cause difficult-to-treat life-threatening infections insusceptible to conventional antibiotic therapy. Hence, the severity of the current scenario necessitates the development of a potent therapeutic agent with a smart strategy. Toward this goal herein, we have explored the potency of membrane-active, amino-acid-conjugated polymers (ACPs) to combat notorious Gram-negative pathogens in combination with intrinsically resistant antibiotic rifampicin. The polymers were able to enhance the antibacterial potency of rifampicin against different drug-resistant Gram-negative bacteria by 4-66 fold. The combination, which consisted of glycine-conjugated polymer, ACP-1 (Gly), and rifampicin was rapidly bactericidal in nature. This combination also exhibited significant potency to disrupt the preformed biofilms of drug-resistant strains of P. aeruginosa and E. coli. More importantly, a negligible propensity of resistance development was observed against this combination, whereas a high level of resistance development was observed against the last-resort antibiotic, colistin. Furthermore, ACP-1 (Gly) displayed noticeably good 50% lethal dosage in different administration routes (LD50 (subcutaneous) > 179 mg/kg and LD50 (intraperitoneal) = 100 mg/kg) in a mouse model. Additionally, ACP-1 (Gly) did not show any adverse effect on mouse skin even at 200 mg/kg. Therefore, the results ensured that the ACP-1 (Gly) is suitable for both topical as well as systemic application. Altogether, the results indicated significant promises of the combination for further development as a therapeutic regimen to tackle the outbreak of critical Gram-negative bacteria.

Small antibacterial molecules highly active against drug-resistant Staphylococcus aureus.

The rapid growth of antibiotic resistance in Staphylococcus aureus coupled with their biofilm forming ability has made the infections difficult to treat with conventional antibiotics. This has created a massive threat towards public health and is a huge concern worldwide. Aiming to address this challenging issue, herein we report a new class of small antibacterial molecules (SAMs) with high antibacterial activity against multidrug-resistant S. aureus. The design principle of the molecules was based on the variation of hydrophobic/hydrophilic balance through incorporation of two quaternary ammonium groups, ethanol moieties, non-peptidic amide bonds and aliphatic chains. The lead compound, identified through a comprehensive analysis of structure-activity relationships, displayed high activity against clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) with MIC values in the range of 1-4 µg mL-1. More importantly, this compound was capable of killing stationary phase bacteria and disrupting established biofilms of MRSA. Additionally, the compound revealed minimum toxicity towards human erythrocytes (HC50 = 577 µg mL-1) and did not show significant toxicity towards mammalian cells (MDCK and A549) up to 128 µg mL-1. Remarkably, the incorporation of non-peptidic amide bonds made the compounds less susceptible to degradation in human plasma, serum and mouse liver homogenate. Taken together, the results therefore indicate great promise for this class of molecules to be developed as potent antibacterial agents in treating infections caused by drug-resistant S. aureus.

Recent Progress in Polymer Research to Tackle Infections and Antimicrobial Resistance.

Global health is increasingly being threatened by the rapid emergence of drug-resistant microbes. The ability of these microbes to form biofilms has further exacerbated the scenario leading to notorious infections that are almost impossible to treat. For addressing this clinical threat, various antimicrobial polymers, polymer-based antimicrobial hydrogels and polymer-coated antimicrobial surfaces have been developed in the recent past. This review aims to discuss such polymer-based antimicrobial strategies with a focus on their current advancement in the field. Antimicrobial polymers, whose designs are inspired from antimicrobial peptides (AMPs), are described with an emphasis on structure-activity analysis. Additionally, antibiofilm activity and in vivo efficacy are delineated to elucidate the real potential of these antimicrobial polymers as possible therapeutics. Antimicrobial hydrogels, prepared from either inherently antimicrobial polymers or biocide-loaded into polymer-derived hydrogel matrix, are elaborated followed by various strategies to engineer polymer-coated antimicrobial surfaces. In the end, the current challenges are accentuated along with future directions for further expansion of the field toward tackling infections and antimicrobial resistance.

Structure and stability of noble gas bound EX3+ compounds (E = C, Ge, Sn, Pb; X = H, F, Cl, Br).

It has been analyzed at the MP2/def2-QZVPPD level whether EX3+ (E = C-Pb; X = H, F-Br) can bind noble gas atoms. Geometrical and electronic structures, dissociation energy values, thermochemical parameters, natural bond order, electron density, and energy decomposition analyses highlight the possibility of such noble gas bound EX3+ compounds. Except He and Ne, the other heavier congeners of this family make quite strong bonds with E. In fact, the dissociations of Ar-Rn bound analogues turn out to be endergonic in nature at 298 K, except in the cases of ArGe Cl3+, Ar/KrGeBr3+, and ArSnBr3+. GeH3+ and EF3+ (E = Ge-Pb) can even bind two Ng atoms with reasonably high dissociation energy. As the pz orbital of the E center in EX3+ plays a crucial role in its binding with the noble gas atoms, the effect of the π back-bonding causing X → E electron transfer ought to be properly understood. Due to the larger back-donation, the Ng binding ability of EX3+ gradually decreases along F to Br. EH2+ and the global minimum HE(+…) H2 (E = Sn, Pb) complexes are also able to bind Ar-Rn atoms quite effectively. The NgE bonds in Ar-Rn bound CH3+, GeH3+, and EF3+ (E = Ge-Pb) and Xe/RnE bonds in NgECl3+ and NgEBr3+ (E = Ge, Sn) are mainly of covalent type.