Exploring the Correlation of Dynamic Surface Tension with Antimicrobial Activities of Quaternary Ammonium-Based Disinfectants.

Quaternary ammonium compound (QAC) disinfectants represent one of our first lines of defense against pathogens. Their inhibitory and bactericidal activities are usually tested through minimum inhibitory concentration (MIC) and time-kill assays, but these assays can become cumbersome when screening many compounds. We investigated how the dynamic surface tension (DST) measurements of QACs correlate with these antimicrobial activities by testing a panel of potent and structurally varied QACs against the gram-positive Staphylococcus aureus and the gram-negative Pseudomonas aeruginosa. We found that DST values correlated well with bactericidal activity in real-world disinfection conditions but not with MIC values. Moreover, no correlation between these two antimicrobial activities of QACs (bactericidal and inhibition) was observed. In addition, we observed that the bactericidal activity of our QAC panel against the gram-negative P. aeruginosa was severely affected in the presence of hard water. Interestingly, we found that the counterion of the QAC affects the killing of bacteria in these conditions, a phenomenon not observed in most MIC assessments. Moreover, some of our best-in-class QACs show enhanced bactericidal activity when combined with a commercially available QAC. In conclusion, we determined that an intrinsic physical property of QACs (DST) can be used as a technique to screen for bactericidal activity of QACs in conditions that mimic real-world disinfection conditions.

Chimeric Amphiphilic Disinfectants: Quaternary Ammonium/Quaternary Phosphonium Hybrid Structures.

Cationic biocides play a crucial role in the disinfection of domestic and healthcare surfaces. Due to the rise of bacterial resistance towards common cationic disinfectants like quaternary ammonium compounds (QACs), the development of novel actives is necessary for effective infection prevention and control. Toward this end, a series of 15 chimeric biscationic amphiphilic compounds, bearing both ammonium and phosphonium residues, were prepared to probe the structure and efficacy of mixed cationic ammonium-phosphonium structures. Compounds were obtained in two steps and good yields, with straightforward and chromatography-free purifications. Antibacterial activity evaluation of these compounds against a panel of seven bacterial strains, including two MRSA strains as well as opportunistic pathogen A. baumannii, were encouraging, as low micromolar inhibitory activity was observed for multiple structures. Alkyl chain length on the ammonium group was, as expected, a major determinant of bioactivity. In addition, high therapeutic indexes (up to 125-fold) for triphenyl phosphonium-bearing amphiphiles were observed when comparing antimicrobial activity to mammalian cell lysis activity.

One-pot fabrication of Ag @Ag2O core-shell nanostructures for biosafe antimicrobial and antibiofilm applications.

Microbial contamination is one of the major dreadful problems that raises hospitalization, morbidity and mortality rates globally, which subsequently obstructs socio-economic progress. The continuous misuse and overutilization of antibiotics participate mainly in the emergence of microbial resistance. To circumvent such a multidrug-resistance phenomenon, well-defined nanocomposite structures have recently been employed. In the current study, a facile, novel and cost-effective approach was applied to synthesize Ag@Ag2O core-shell nanocomposites (NCs) via chemical method. Several techniques were used to determine the structural, morphological, and optical characteristics of the as-prepared NCs. XRD, Raman, FTIR, XPS and SAED analysis revealed a crystalline hybrid structure of Ag core and Ag2O shell. Besides, SEM and HRTEM micrographs depicted spherical nanoparticles with size range of 19-60 nm. Additionally, zeta potential and fluorescence spectra illustrated aggregated nature of Ag@Ag2O NCs by - 5.34 mV with fluorescence emission peak at 498 nm. Ag@Ag2O NCs exhibited higher antimicrobial, antibiofilm, and algicidal activity in dose-dependent behavior. Interestingly, a remarkable mycocidal potency by 50 µg of Ag@Ag2O NCs against Candida albican; implying promising activity against COVID-19 white fungal post-infections. Through assessing cytotoxicity, Ag@Ag2O NCs exhibited higher safety against Vero cells than bulk silver nitrate by more than 100-fold.

Polyphenol stabilized copper nanoparticle formulations for rapid disinfection of bacteria and virus on diverse surfaces.

Rapid and sustained disinfection of surfaces is necessary to check the spread of pathogenic microbes. The current study proposes a method of synthesis and use of copper nanoparticles (CuNPs) for contact disinfection of pathogenic microorganisms. Polyphenol stabilized CuNPs were synthesized by successive reductive disassembly and reassembly of copper phenolic complexes. Morphological and compositional characterization by transmission electron microscope (TEM), selected area diffraction and electron energy loss spectroscopy revealed monodispersed spherical (ϕ5-8 nm) CuNPs with coexisting Cu, Cu(I) and Cu (II) phases. Various commercial grade porous and non-porous substrates, such as, glass, stainless steel, cloth, plastic and silk were coated with the nanoparticles. Complete disinfection of 107copies of surrogate enveloped and non-enveloped viruses: bacteriophage MS2, SUSP2, phi6; and gram negative as well as gram positive bacteria:Escherichia coliandStaphylococcus aureuswas achieved on most substrates within minutes. Structural cell damage was further analytically confirmed by TEM. The formulation was well retained on woven cloth surfaces even after repeated washing, thereby revealing its promising potential for use in biosafe clothing. In the face of the current pandemic, the nanomaterials developed are also of commercial utility as an eco-friendly, mass producible alternative to bleach and alcohol based public space sanitizers used today.

A Novel N-Halamine Biocidal Nanofibrous Membrane for Chlorine Rechargeable Rapid Water Disinfection Applications.

Disinfecting pathogenic contaminated water rapidly and effectively on sites is one of the critical challenges at point-of-use (POU) situations. Currently available technologies are still suffering from irreversible depletion of disinfectants, generation of toxic by-products, and potential biofouling problems. Herein, we developed a chlorine rechargeable biocidal nanofibrous membrane, poly(acrylonitrile-co-5-methyl-5-(4'-vinylphenyl)imidazolidine-2,4-dione) (P(AN-VAPH)), via a combination of a free radical copolymerization reaction and electrospun technology. The copolymer exhibits good electrospinnability and desirable mechanical properties. Also, the 5-methyl-5-(4'-vinylphenyl)imidazolidine-2,4-dione (VAPH) moieties containing unique hydantoin structures are able to be chlorinated and converted to halamine structures, enabling the P(AN-VAPH) nanofibrous membrane with rapid and durable biocidal activity. The chlorinated P(AN-VAPH) nanofibrous membranes showed intriguing features of unique 3D morphological structures with large specific surface area, good mechanical performance, rechargeable chlorination capacity (>5000 ppm), long-term durability, and desirable biocidal activity against both bacteria and viruses (>99.9999% within 2 min of contact). With these attributes, the chlorinated P(AN-VAPH) membranes demonstrated promising disinfecting efficiency against concentrated bacteria-contaminated water during direct filtration applications with superior killing capacity and high flowing flux (5000 L m-2 h-1).

Novel Phenyl-Based Bis-quaternary Ammonium Compounds as Broad-Spectrum Biocides.

Herein we report the synthesis and microbiological evaluation of novel phenyl based bis-quaternary ammonium compounds (bis-QACs). Using a simple 2-step synthetic route from dibromo- and dihydroxybenzenes, we obtained a structurally diverse broad panel of bis-QACs with topologically distinct bridging connections between pyridinium heads. Selected analogs possessed potent broad-spectrum biocidal activity against both bacterial and fungal pathogens: methicillin-resistant Staphylococcus aureus (ATCC 43300); Escherichia coli (ATCC 25922), Klebsiella pneumonia (ATCC 700603), Acinetobacter baumannii (ATCC 19606), Pseudomonas aeruginosa (ATCC 27853), Candida albicans (ATCC 90028), Cryptococcus neoformans var. grubii (ATCC 208821). Promising compounds displayed minimum inhibitory concentrations (MIC) values ≤0.25 µg/mL alongside improved cytotoxicity and hemolytic profiles compared to modern antiseptics. Thus, synthesized bis-QACs represent a promising class of biocides with the potential to replace existing household sanitizers.

Novel boronium salt exhibits substantial antibacterial activity when compared to a commercial quaternary ammonium disinfectant.

Commercial disinfectants are routinely used to decontaminate surfaces where microbes are expected and unwelcome. Several disinfectants contain quaternary ammonium salts, or "quats", all being derived from ammonium. Quaternary alkyl dimethyl benzyl ammonium chloride or bromide disinfectants are widely available. These compounds are effective in reducing or eliminating bacteria on contaminated nonporous surfaces. A unique benzyl derived boronium salt with strong detergent action has been developed. It demonstrated 4-8X greater antibacterial activity against 3 different bacteria when compared to an equal concentration of a commercial quant disinfectant solution containing alkyl dimethyl benzyl ammonium chloride and alkyl dimethyl ethylbenzyl ammonium chloride. Antibacterial effectiveness of each agent was determined by the minimum inhibitory concentration (MIC) method.

New Promises from an Old Friend: Iodine-Rich Compounds as Prospective Energetic Biocidal Agents.

For a very long time, frequent occurrences of biocrises have wreaked havoc on human beings, animals, and the environment. As a result, it is necessary to develop biocidal agents to destroy or neutralize active agents by releasing large amounts of strong biocides which are obtained upon detonation. Iodine is an efficient biocidal agent for bacteria, fungi, yeasts, viruses, spores, and protozoan parasites, and it is the sole element in the periodic table that can destroy microbes without contaminating the environment. Based on chemical biology, the mechanism of iodine as a bactericide may arise from oxidation and iodination reactions of cellular proteins and nucleic acids. However, because of the high vapor pressure causing elemental iodine to sublime readily at room temperature, it is inconvenient to use this material in its normal solid state directly as a biocidal agent under ambient conditions. Iodine-rich compounds where iodine is firmly bonded in molecules as a C-I or I-O moiety have been observed to be among the most promising energetic biocidal compounds. Gaseous products comprised of large amounts of iodine or iodine-containing components as strong biocides are released in the decomposition or explosion of iodine-rich compounds. Because of the detonation pressure, the iodine species are distributed over a large area greatly improving the efficacy of the system and requiring considerably less effort compared to traditional biocidal methods. The commercially available tetraiodomethane and tetraiodoethene, which possess superb iodine content also have the disadvantages of volatility, light sensitivity, and chemically reactivity, and therefore, are not suitable for use directly as biocidal agents. It is absolutely critical to synthesize new iodine-rich compounds with good thermal and chemical stabilities.In this Account, we describe our strategies for the syntheses of energetic iodine-rich compounds while maintaining the maximum iodine content with concomitant stability and routes for the synthesis of oxygen-containing iodine-rich compounds to improve the oxygen balance and achieve both high-energy and high-iodine content. In the other work, which involves cocrystals, iodine-containing polymers were also summarized. It is hoped that this Account will provide guidelines for the design and syntheses of new iodine-rich compounds and a route for the development of inexpensive, more efficient, and safer iodine-rich antibiological warfare agents of the future.

Nitric Oxide-Releasing Insert for Disinfecting the Hub Region of Tunnel Dialysis Catheters.

The use of tunneled dialysis catheters (TDCs) for patients in need of hemodialysis treatments (HDs) causes a significant number of bloodstream infections (BSIs), with very few viable preventative/treatment methods. Use of antibiotics is relatively ineffective due to the development of multidrug-resistant bacterial strains and the inability to penetrate bacterial biofilms. Nitric oxide (NO) is an endogenous gas molecule that has broad-spectrum antimicrobial/antibiofilm activity. In this study, the potential of creating a NO-releasing insert device that is attached onto the hub region cap of TDCs and locally releases NO within the TDC hub is evaluated for its antimicrobial/antibiofilm effectiveness. The NO-releasing insert contains the natural NO donor S-nitrosoglutathione (GSNO), along with zinc oxide (ZnO) nanoparticles to accelerate NO release from the GSNO, within a short silicone tube that is sealed at both ends and attached to the catheter cap. An in vitro 3-d-long antimicrobial study using catheter hubs yielded >6.6 log reductions of both Pseudomonas aeruginosa and Staphylococcus aureus for the NO-releasing insert device compared to controls. Two 14-d-long sheep studies demonstrated that the NO-releasing insert devices are exceptionally potent at preventing bacteria/biofilm growth on the inner lumen walls of TDCs compared to controls that have no preventative treatment devices as well as implanted TDCs that have commercially available chlorhexidine-treated insert devices placed within the hub regions.

Enhancement of A Cationic Surfactant by Capping Nanoparticles: Synthesis, Characterization and Multiple Applications.

There is scarce information on cationic surfactants' biocidal and corrosion inhbibition effects on Slime-Forming Bacteria (SFB) isolated from oil field formation water. Therefore, this work focused on the the synthesis of a cationic surfactant (CS) to increase its features by capping different metal nanoparticles (zinc, ZnNPs-C-CS; manganese, MnNPs-C-CS and tin, SnNPs-C-CS) and used them as biocides and corrosion inhibitors. The cationic surfactant was synthesized and characterized by Fourier-Transform Infrared (FTIR) and Nuclear Magnetic Resonance (NMR) spectroscopy. Afterwards, different nanoparticles were synthesized, characterized, and exploited to cap by the CS. The CS and the different nanoparticles capped by the CS were tested for their antimicrobial susceptibility against standard bacterial and yeast strains. The synthesized compounds were further evaluated as anti-biofilms agents against positively-developed bacterial biofilms. Moreover, the CS and the ZnNPs-C-CS, MnNPs-C-CS, and SnNPs-C-CS were assessed as potential biocides against SFB, particularly Pseudomonas sp. (isolated from contaminated formation water), and as corrosion inhibitors against cultivated salinity. The results revealed the great effect of the different CS-capped NPs as broad-spectrum antimicrobial and anti-biofilm agents at lower Minimum Inhibitory Concentrations (MICs), Minimum Bactericidal Concentrations (MBCs), Minimum Fungicidal Concentrations (MFCs) and Minimum Biofilm Inhibitory Concentrations (MBICs), and the activities were reported in order of SnNPs-C-CS > MnNPs-C-CS > ZnNPs-C-CS > CS. Furthermore, the ZnNPs-C-CS, MnNPs-C-CS, and SnNPs-C-CS demonstrated biocidal and corrosion inhibition effects against Pseudomonas sp. at a salinity of 3.5% NaCl, with metal corrosion inhibition efficiencies of 88.6, 94.0 and 96.9%, in comparison to a CS efficiency of 85.7%. In conclusion, the present work provides a newly synthesized cationic surfactant and has enhanced its antimicrobial and its metal corrosion inhibition effects by capping different nanoparticles, and it has been successfully applied against slime-forming bacteria at a salinity of 3.5% NaCl.

Overcoming environmental problems of biocides: Synthetic bile acid derivatives as a sustainable alternative.

Marine biofouling represents a global economic and ecological challenge. Some marine organisms produce bioactive metabolites, such as steroids, that inhibit the settlement and growth of fouling organisms. The aim of this work was to explore bile acids as a new scaffold with antifouling (AF) activity by using chemical synthesis to produce a series of bile acid derivatives with optimized AF performance and understand their structure-activity relationships. Seven bile acid derivatives were successfully synthesized in moderate to high yields, and their structures were elucidated through spectroscopic methods. Their AF activities were tested against both macro- and microfouling communities. The most potent bile acid against the settlement of Mytilus galloprovincialis larvae was the methyl ester derivative of cholic acid (10), which showed an EC50 of 3.7 µM and an LC50/EC50 > 50 (LC50 > 200 µM) in AF effectiveness vs toxicity studies. Two derivatives of deoxycholic acid (5 and 7) potently inhibited the growth of biofilm-forming marine bacteria with EC50 values < 10 µM, and five bile acids (1, 5, and 7-9) potently inhibited the growth of diatoms, showing EC50 values between 3 and 10 µM. Promising AF profiles were achieved with some of the synthesized bile acids by combining antimacrofouling and antimicrofouling activities. Initial studies on the incorporation of one of these promising bile acid derivatives in polymeric coatings, such as a marine paint, demonstrated the ability of these compounds to generate coatings with antimacrofouling activity.

Disinfectant Efficacy: Understanding the Expectations and How to Design Effective Studies That Include Leveraging Multi-Site Data to Drive an Efficient Program.

For manufacturers of both sterile and nonsterile pharmaceuticals, there is an expectation that the manufacturing process is performed in a manner that prevents extraneous contamination so that the products are provided in a safe, integral, pure, and unadulterated form. As part of that process, cleaning and disinfection are an absolute necessity. Although cleaning and disinfection support control of microbial contamination through preventive and corrective action, specific compendia methods do not currently exist. The intent of this paper is to provide a general guidance on how to perform disinfectant efficacy validation and implementation. This includes how to make sure the concepts are understood, how to interpret facility data and utilize it to demonstrate control awareness for your facilities, and how to leverage the data to reduce redundancies in validation or verification. This paper represents the thoughts and best practices of the authoring team and their respective companies and provides an efficient way to qualify disinfectants without impacting the quality of the study. If you choose to follow the recommendations in this paper, you must ensure that the appropriate rationale is sound and the scientific data is documented. It is the belief of the authoring team that only then will this approach meet regulatory requirements.

Electrochemical Preparation of Synergistic Nanoantimicrobials.

The rapid spreading of resistance among common bacterial pathogens towards the misused antibiotics/disinfectant agents has drawn much attention worldwide to bacterial infections. In light of this, the present work aimed at the realization of core-shell nanoparticles possessing remarkable antimicrobial properties thanks to the synergistic action of the metal core and the disinfectant shell. Copper nanoparticles stabilized by benzalkonium chloride were prepared, characterized, and implemented in poly-vinyl-methyl ketone to obtain nanoantimicrobial composite coatings. Bioactivity tests are reported, proving the excellent disinfectant properties of the proposed nanomaterials, as compared to one of the well-known and strongest silver-based nanoantimicrobials. Applications are also briefly described.

Diclofenac conjugates with biocides through silver(I) ions (CoMeD's); Development of a reliable model for the prediction of anti-proliferation of NSAID's-silver formulations.

The conjugation of diclofenac (DICLH), a Non-Steroidal Anti-inflammatory Drug (NSAID), with biocides such as dimethyl sulfoxide (DMSO) and triphenylphosphine (TPP), through silver(I) ions, results into the chemical [Agn(DICL)n(L)m]k (L = DMSO and n = 2, m = 2, k = infinite (1); L = TPP and n = 1, m = 2, k = 1 (2)). The compounds were characterized by m.p., FT-IR, UV-vis and 1H NMR spectroscopic techniques. The crystal and molecular structures of 1-2 were determined by X-ray crystallography. The in vitro cytotoxic activity of 1-2 against the human breast adenocarcinoma cancer cells MCF-7 (hormone dependent) and MDA-MB-231 (hormone independent) reveals that the 1 inhibits the MCF-7 rather than the MDA-MB-231 cells, suggesting hormone mimetic behaviour. Compound 2 inhibits both cancerous cell lines, stronger than cisplatin. Both compounds inhibit MCF-7 cells migration. Compounds 1-2, exhibit, lower toxicity against fetal lung fibroblast (MRC-5) cells than cisplatin. Their genotoxicity was evaluated on MRC-5 cells. The molecular mechanism of 1-2 against MCF-7 cells was clarified by (i) their cell cycle arrest study (ii) their mitochondrial membrane permeability (iii) their binding affinity towards Calf Thymus (CT)-DNA and (iv) their inhibitory activity against the enzyme lipoxygenase (LOX). Regression analysis of the data obtained for [Ag(NSAID)(Ar3P)m] (NSAID = p­hydroxy­benzoic acid (p-HO-BZAH), salicylic acid (SALH2), aspirin (ASPH), naproxen (NAPRH), nimesulide (NIMH); L = TPP, Tri(p­tolyl)phosphine (TPTP), Tri(o­tolyl)phosphine (TOTP), Tri(m­tolyl)phosphine (TMTP); m = 2 or 3) and [Ag(DICL)2(DMSO)2]k (k = infinite) was performed. Considering the biological results (IC50) as dependent variable a theoretical equation is obtained for these compounds. The calculated IC50 values are compared satisfactorily with the corresponding experimental inhibitory activity of the complexes.

Control of Biohazards: A High Performance Energetic Polycyclized Iodine-Containing Biocide.

Biohazards and chemical hazards as well as radioactive hazards have always been a threat to human health. The search for solutions to these problems is an ongoing worldwide effort. In order to control biohazards by chemical methods, a synthetically useful fused tricyclic iodine-rich compound, 2,6-diiodo-3,5-dinitro-4,9-dihydrodipyrazolo [1,5- a:5',1'- d][1,3,5]triazine (5), with good detonation performance was synthesized, characterized, and its properties determined. This compound which acts as an agent defeat weapon has been shown to destroy certain microorganisms effectively by releasing iodine after undergoing decomposition or combustion. The small iodine residues remaining will not be deleterious to human life after 1 month.

Facile synthesis of magnetic disinfectant immobilized with silver ions for water pathogenic microorganism's deactivation.

One-pot synthesis of a new magnetic disinfectant was achieved through the polymerization of thiourea and formaldehyde in the presence of magnetite nanoparticles (MTUF). The obtained magnetic chelating resin was loaded with Ag(I) ions. This material was tested as a disinfectant for water pathogenic microorganism's deactivation. The toxicity of MTUF before and after Ag(I) loading was estimated. The antimicrobial activity tests of MTUF-Ag were carried out against Escherichia coli, Salmonella Typhimurium, and Pseudomonas aeruginosa as examples of Gram-negative bacteria; Listeria monocytogenes, Staphylococcus aureus, Enterococcus faecalis, and Bacillus subtilis as examples of Gram-positive bacteria; and Candida albicans as representative for fungi. The results showed that the minimum inhibitory dosage (MID) of MTF-Ag against Escherichia coli, Salmonella Typhimurium, Listeria monocytogenes, Staphylococcus aureus, and mixed culture were 1.5, 2.0, 1.0, 1.5, and 1.5 mg/mL, respectively, after 40 min of contact time. While C. albicans was more resistant to the magnetic disinfectant, only three log reductions were done at 2.5 mg/mL. The studied MTUF-Ag was successfully tested for water and wastewater pathogenic microorganism's deactivation. It can be concluded that MTUF-Ag could be a good candidate for water disinfection.

Eco-friendly approach to the synthesis of silver nanoparticles and their antibacterial activity against Staphylococcus spp. and Escherichia coli.

The aim of this study was to assess bactericidal properties of nanosilver obtained with ascorbic acid (vitamin C) as a reducing substance, against environmental strains of Gram-positive (Staphylococcus) and Gram-negative bacteria (Escherichia coli). Silver nanoparticles were obtained by a simple and fast method of chemical reduction in mild synthesis condition using substrates not classified as dangerous and commonly found in plants. Bacterial susceptibility to nanosilver was determined using the disk-diffusion method. Gram-positive bacteria were less susceptible to bactericidal action of nanosilver and minimum inhibitory concentration was higher for these bacteria. However, susceptibility of individual isolates of different species to nanosilver was very diverse. The range of growth inhibition zones indicates that the resistance to different concentrations of nanosilver was a strain-characteristic, not species-related feature. The study of effective nanomaterials synthesis and applicability appears to be an extremely important element in the development of nanotechnology, especially in terms of the risks assessment. Obtained results have a real chance to be an important step toward creating a new generation of disinfectants without toxic effects on the environment and higher organisms.

Pentadecanal inspired molecules as new anti-biofilm agents against Staphylococcus epidermidis.

Staphylococcus epidermidis, a harmless human skin colonizer, is a significant nosocomial pathogen in predisposed hosts because of its capability to form a biofilm on indwelling medical devices. In a recent paper, the purification and identification of the pentadecanal produced by the Antarctic bacterium Pseudoalteromonas haloplanktis TAC125, able to impair S. epidermidis biofilm formation, were reported. Here the authors report on the chemical synthesis of pentadecanal derivatives, their anti-biofilm activity on S. epidermidis, and their action in combination with antibiotics. The results clearly indicate that the pentadecanal derivatives were able to prevent, to a different extent, biofilm formation and that pentadecanoic acid positively modulated the antimicrobial activity of the vancomycin. The cytotoxicity of these new anti-biofilm molecules was tested on two different immortalized eukaryotic cell lines in view of their potential applications.

Biocidal properties of maltose reduced silver nanoparticles against American foulbrood diseases pathogens.

Bee disease caused by spore-forming Paenibacillus larvae and Paenibacillus alvei is a serious problem for honey production. Thus, there is an ongoing effort to find an effective agent that shows broad biocidal activity with minimal environmental hazard. In this study, the biocidal effect of maltose reduced silver nanoparticles (AgNPs) is evaluated against American foulbrood and European foulbrood pathogens. The results demonstrate that the maltose reduced AgNPs are excellent short and long-term biocides against P. larvae isolates. The long-term effect suggests that the Ag+ ions are released from the AgNPs with increasing time in a controlled manner.

Ester- and amide-containing multiQACs: Exploring multicationic soft antimicrobial agents.

Quaternary ammonium compounds (QACs) are ubiquitous antiseptics whose chemical stability is both an aid to prolonged antibacterial activity and a liability to the environment. Soft antimicrobials, such as QACs designed to decompose in relatively short times, show the promise to kill bacteria effectively but not leave a lasting footprint. We have designed and prepared 40 soft QAC compounds based on both ester and amide linkages, in a systematic study of mono-, bis-, and tris-cationic QAC species. Antimicrobial activity, red blood cell lysis, and chemical stability were assessed. Antiseptic activity was strong against a panel of six bacteria including two MRSA strains, with low micromolar activity seen in many compounds; amide analogs showed superior activity over ester analogs, with one bisQAC displaying average MIC activity of ∼1µM. For a small subset of highly bioactive compounds, hydrolysis rates in pure water as well as buffers of pH =4, 7, and 10 were tracked by LCMS, and indicated good stability for amides while rapid hydrolysis was observed for all compounds in acidic conditions.