Isoamphipathic antibacterial molecules regulating activity and toxicity through positional isomerism.

Peptidomimetic antimicrobials exhibit a selective interaction with bacterial cells over mammalian cells once they have achieved an optimum amphiphilic balance (hydrophobicity/hydrophilicity) in the molecular architecture. To date, hydrophobicity and cationic charge have been considered the crucial parameters to attain such amphiphilic balance. However, optimization of these properties is not enough to circumvent unwanted toxicity towards mammalian cells. Hence, herein, we report new isoamphipathic antibacterial molecules (IAMs: 1-3) where positional isomerism was introduced as one of the guiding factors for molecular design. This class of molecules displayed good (MIC = 1-8 µg mL-1 or µM) to moderate [MIC = 32-64 µg mL-1 (32.2-64.4 µM)] antibacterial activity against multiple Gram-positive and Gram-negative bacteria. Positional isomerism showed a strong influence on regulating antibacterial activity and toxicity for ortho [IAM-1: MIC = 1-32 µg mL-1 (1-32.2 µM), HC50 = 650 µg mL-1 (654.6 µM)], meta [IAM-2: MIC = 1-16 µg mL-1 (1-16.1 µM), HC50 = 98 µg mL-1 (98.7 µM)] and para [IAM-3: MIC = 1-16 µg mL-1 (1-16.1 µM), HC50 = 160 µg mL-1 (161.1 µM)] isomers. Co-culture studies and investigation of membrane dynamics indicated that ortho isomer, IAM-1 exerted more selective activity towards bacterial over mammalian membranes, compared to meta and para isomers. Furthermore, the mechanism of action of the lead molecule (IAM-1) has been characterized through detailed molecular dynamics simulations. In addition, the lead molecule displayed substantial efficacy against dormant bacteria and mature biofilms, unlike conventional antibiotics. Importantly, IAM-1 exhibited moderate in vivo activity against MRSA wound infection in a murine model with no detectable dermal toxicity. Altogether, the report explored the design and development of isoamphipathic antibacterial molecules to establish the role of positional isomerism in achieving selective and potential antibacterial agents.

An easy-to-use antimicrobial hydrogel effectively kills bacteria, fungi, and influenza virus.

Various drug resistant pathogens such as bacteria, fungi and viruses enter a host through different routes, which can lead to health-related problems and even fatalities. Propagation of these infectious microbes majorly occurs through the mucosal openings or upon topical contact. To curb their transmission or to cure infections associated with these pathogens, herein we describe the development of an antimicrobial hydrogel, based on a water soluble quaternary lipophilic polyethyleneimine derivative (QPEINH-C6). The cationic polymer QPEINH-C6 exhibited antibacterial activity against drug-resistant Gram-positive bacteria (MIC = 10-62 µg mL-1) and Gram-negative bacteria (MIC = 117-123 µg mL-1). The derivative showed killing of human pathogenic fungi (MIC = 58-67 µg mL-1), including their clinical isolates. The rapid bactericidal and fungicidal nature were confirmed from the fast inactivation kinetics of bacterial cells (methicillin resistant S. aureus and vancomycin resistant S. aureus) within 3-6 hours and C. albicans within 1 h with ∼5-6 log reduction in the microbial burden. This antibacterial and antifungal cationic polymer was then used to construct an antimicrobial shear-thinning hydrogel (Bacfuvir), through non-covalent crosslinking with biocompatible gellan and polyvinyl alcohol (PVA). This hydrogel displayed ∼5-7 log reduction of numerous multidrug-resistant bacteria and their stationary phase cells which are insusceptible to conventional antibiotics. In addition, >99.9 % viable bacterial burden was reduced from preformed biofilm matrices of drug-resistant bacteria. Alongside, fluconazole-resistant C. albicans strains were killed completely within 15-60 min upon exposure to Bacfuvir gel. Most importantly, MRSA and C. albicans cells were reduced (3-4 log) in polymicrobial biofilms after hydrogel treatment. The hydrogel exhibited 99.9 % reduction of influenza viruses in a rapid manner. Due to the biocompatibility of Bacfuvir gel on topical application in a murine model and easy administration owing to its shear-thinning behaviour, this hydrogel can markedly contribute to mitigating drug-resistant bacterial, fungal and viral infections in healthcare settings.

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).