Kevin Minbiole

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Organization: Villanova University

Department: Department of Chemistry

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TOPICS

Applied Chemistry

Bactericide

Chemicals
References

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

Co-reporter:Ryan A. Allen, Megan C. Jennings, Myles A. Mitchell, Saleh E. Al-Khalifa, William M. Wuest, Kevin P.C. Minbiole

Bioorganic & Medicinal Chemistry Letters 2017 Volume 27, Issue 10(Issue 10) pp:

Publication Date(Web):15 May 2017

DOI:10.1016/j.bmcl.2017.03.077

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 ∼1 μM. 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.Download high-res image (70KB)Download full-size image

Identification of Bufadienolides from the Boreal Toad, Anaxyrus boreas, Active Against a Fungal Pathogen

Co-reporter:Kelly Barnhart;Megan E. Forman;Thomas P. Umile;Jordan Kueneman

Microbial Ecology 2017 Volume 74( Issue 4) pp:990-1000

Publication Date(Web):19 June 2017

DOI:10.1007/s00248-017-0997-8

Amphibian granular glands provide a wide range of compounds on the skin that defend against pathogens and predators. We identified three bufadienolides—the steroid-like compounds arenobufagin, gamabufotalin, and telocinobufagin—from the boreal toad, Anaxyrus boreas, through liquid chromatography mass spectrometry (LC/MS). Compounds were detected both after inducing skin gland secretions and in constitutive mucosal rinses from toads. We described the antimicrobial properties of each bufadienolide against Batrachochytrium dendrobatidis (Bd), an amphibian fungal pathogen linked with boreal toad population declines. All three bufadienolides were found to inhibit Bd growth at similar levels. The maximum Bd inhibition produced by arenobufagin, gamabufotalin, and telocinobufagin were approximately 50%, in contrast to the complete Bd inhibition shown by antimicrobial skin peptides produced by some amphibian species. In addition, skin mucus samples significantly reduced Bd viability, and bufadienolides were detected in 15 of 62 samples. Bufadienolides also appeared to enhance growth of the anti-Bd bacterium Janthinobacterium lividum, and thus may be involved in regulation of the skin microbiome. Here, we localized skin bacteria within the mucus layer and granular glands of toads with fluorescent in situ hybridization. Overall, our results suggest that bufadienolides can function in antifungal defense on amphibian skin and their production is a potentially convergent trait similar to antimicrobial peptide defenses found on the skin of other species. Further studies investigating bufadienolide expression across toad populations, their regulation, and interactions with other components of the skin mucosome will contribute to understanding the complexities of amphibian immune defense.

StructureResistance Relationships: Interrogating Antiseptic Resistance in Bacteria with Multicationic Quaternary Ammonium Dyes

Co-reporter:Megan E. Forman;Madison H. Fletcher;Megan C. Jennings;Stephanie M. Duggan; Kevin P. C. Minbiole; William M. Wuest

ChemMedChem 2016 Volume 11( Issue 9) pp:958-962

Publication Date(Web):

DOI:10.1002/cmdc.201600095

Abstract

Bacterial resistance toward commonly used biocides is a widespread yet underappreciated problem, one which needs not only a deeper understanding of the mechanisms by which resistance proliferates, but also means for mitigation. To advance our understanding of this issue, we recognized a polyaromatic structural core analogous to activators of QacR, a negative transcriptional regulator of the efflux pump QacA, and envisioned a series of quaternary ammonium compounds (QACs) based on this motif. Using commercially available dye scaffolds, we synthesized and evaluated the antimicrobial activity of 52 novel QACs bearing 1–3 quaternary ammonium centers. Striking differences in antimicrobial activity against bacteria bearing QAC resistance genes have been observed, with up to a 125-fold increase in minimum inhibitory concentration (MIC) for select structures against bacteria known to bear efflux pumps. Based on these findings, general trends in structure–resistance relationships have been identified, laying the groundwork for future mechanistic studies.

From antimicrobial activity to mechanism of resistance: the multifaceted role of simple quaternary ammonium compounds in bacterial eradication

Co-reporter:Kevin P.C. Minbiole, Megan C. Jennings, Laura E. Ator, Jacob W. Black, Melissa C. Grenier, Jade E. LaDow, Kevin L. Caran, Kyle Seifert, William M. Wuest

Tetrahedron 2016 Volume 72(Issue 25) pp:3559-3566

Publication Date(Web):23 June 2016

DOI:10.1016/j.tet.2016.01.014

Quaternary ammonium compounds (QACs) are a prominent class of antibacterial agents. Drawing inspiration from commercial disinfectants and antimicrobial natural products, we have derivatized structurally diverse tertiary amines to generate several different classes of QACs. We have synthesized over 200 QACs, many of which exhibit potent antibacterial and antibiofilm activity. Analysis of the structure–activity relationship of our compounds have led to the facile production of inexpensive QACs that display ∼1 μM MIC against a suite of bacteria, and furthermore do not appear to trigger bacterial resistance systems in methicillin-resistant Staphylococcus aureus (MRSA).

The Petasis-Ferrier rearrangement: developments and applications

Co-reporter:Emily C Minbiole and Kevin P C Minbiole

The Journal of Antibiotics 2016 69(4) pp:213-219

Publication Date(Web):January 6, 2016

DOI:10.1038/ja.2015.136

In the mid-1990s, Petasis reexamined a promising but infrequently used rearrangement strategy, the so-called Ferrier-type-II reaction, and provided it with a modern update. Previously, Ferrier had developed a strategy where carbohydrate derivatives would undergo a fragmentation/aldol-type recombination sequence, generating a carbocycle, albeit under the promotion of stoichiometric mercury salts. Petasis’ new variant showed the promise to effectively and stereoselectively convert a range of cyclic vinyl acetals to useful tetrahydrofurans and tetrahydropyrans, using less toxic promoters. Since these first reports, the ‘Petasis-Ferrier rearrangement’ has represented a vibrant area of research and innovation for organic chemists. With numerous applications in complex natural product total synthesis, the utility of the reaction has been resoundingly established. Recent developments have extended the reaction to a broader synthetic context, allowing for in situ generation of rearrangement substrates and more liberal interpretation of what fragmentation/recombination reactions warrant the designation of a Petasis-Ferrier rearrangement.

Organic synthesis in the Smith Group: a personal selection of a dozen lessons learned at the University of Pennsylvania

Co-reporter:Kevin P C Minbiole

The Journal of Antibiotics 2016 69(4) pp:192-202

Publication Date(Web):March 2, 2016

DOI:10.1038/ja.2016.21

The passionate study of the complex and ever-evolving discipline of organic synthesis over more than a four-decade span is certain to elucidate meaningful and significant lessons. Over this period, Amos B. Smith III, the Rhodes–Thompson Professor of Chemistry and Member of the Monell Chemical Senses Center at the University of Pennsylvania, has mentored well over 100 doctoral and masters students, more than 200 postdoctoral associates and numerous undergraduates, in addition to collaborating with a wide spectrum of internationally recognized scholars. His research interests, broadly stated, comprise complex molecule synthesis, the development of new, versatile and highly effective synthetic methods, bioorganic and medicinal chemistry, peptide mimicry chemistry and material science. Each area demands a high level of synthetic design and execution. United by a passion to unlock the secrets of organic synthesis, and perhaps of Nature itself, innumerable lessons have been, and continue to be, learned by the members of the Smith Group. This lead article in a Special Issue of the Journal of Antibiotics affords an opportunity to share some of those lessons learned, albeit a small selection of personal favorites.

Beyond paraquats: Dialkyl 3,3′- and 3,4′-bipyridinium amphiphiles as antibacterial agents

Co-reporter:Laura E. Ator, Megan C. Jennings, Amanda R. McGettigan, Jared J. Paul, William M. Wuest, Kevin P.C. Minbiole

Bioorganic & Medicinal Chemistry Letters 2014 Volume 24(Issue 16) pp:3706-3709

Publication Date(Web):15 August 2014

DOI:10.1016/j.bmcl.2014.07.024

Dialkyl 4,4′-bipyridinium compounds, known as ‘paraquats’ (PQs), have a long history of use as herbicides, as redox indicators, and more recently as potent antibacterial agents. However, due to their ability to form reactive oxygen species (ROS) in vivo, PQs are also known to be toxic. We proposed that altering the electrochemical properties of PQ, specifically by preparing isomeric bipyridinium structures with 3,3′- and 3,4′-substitution of the nitrogen heteroatoms on the biaryl core, would maintain antibacterial activity, yet decrease toxicity. We have thus prepared a series of 17 amphiphiles, dubbed ‘metaquat’ (MQ) and ‘parametaquat’ (PMQ), respectively, and investigated their antibacterial and electrochemical properties. Optimal inhibition of bacterial growth was observed in symmetric, biscationic structures; minimum inhibitory concentration (MIC) values measured as low as 0.5 μM against both Gram-positive and Gram-negative bacteria for the compound PMQ-11,11. Electrochemical analysis demonstrated the redox properties of the dialkyl 3,3′- and 3,4′-bipyridinium amphiphiles to be distinct from those of the 4,4′-bipyridinium isomer. Thus MQ and PMQ amphiphiles maintain the strong antibacterial activity of the PQ isomers, but show promise for reduced ROS toxicity.

Nonlethal amphibian skin swabbing of cutaneous natural products for HPLC fingerprinting

Co-reporter:Thomas P. Umile, Patrick J. McLaughlin, Kendall R. Johnson, Shaya Honarvar, Alison L. Blackman, Elizabeth A. Burzynski, Robert W. Davis, Thais L. Teotonio, Gail W. Hearn, Christine A. Hughey, Anthony F. Lagalante and Kevin P. C. Minbiole

Analytical Methods 2014 vol. 6(Issue 10) pp:3277-3284

Publication Date(Web):28 Mar 2014

DOI:10.1039/C4AY00566J

Small organic molecules found on the skin of amphibians may help impart resistance to pathogens, such as the lethal fungus Batrachochytrium dendrobatidis. The study of these compounds has traditionally required euthanasia of the amphibian, followed by chemical extraction of excised skin. As an alternative method, we report the development and assessment of a non-lethal technique using foam-tipped swabs and HPLC analysis to directly isolate and characterize small molecules found on the skin of amphibians. This protocol was field-tested on Bioko Island, Equatorial Guinea with forty-seven frogs (representing 14 native species). Multiple species (particularly Afrixalus paradorsalis and Didynamipus sjostedti) carried sets of species-specific compounds (i.e., a chromatographic fingerprint). A principal coordinate analysis (PCO) of the commonly occurring compounds detected across all species revealed a significant relationship between chromatographic profile and species for all swab samples.

TMEDA-derived biscationic amphiphiles: An economical preparation of potent antibacterial agents

Co-reporter:Jacob W. Black, Megan C. Jennings, Julianne Azarewicz, Thomas J. Paniak, Melissa C. Grenier, William M. Wuest, Kevin P.C. Minbiole

Bioorganic & Medicinal Chemistry Letters 2014 Volume 24(Issue 1) pp:99-102

Publication Date(Web):1 January 2014

DOI:10.1016/j.bmcl.2013.11.070

Bis-alkylated derivatives of N,N,N′,N′-tetramethylethylenediamine (TMEDA) represent a well-known class of versatile biscationic amphiphiles, owing to their low cost and ease of preparation. Asymmetric TMEDA derivatives, however, have been studied significantly less, particularly in regards to their antimicrobial properties. We have thus prepared a series of 36 mono- and bis-alkylated TMEDA derivatives to evaluate their inhibition of bacterial growth. This series of compounds showed low micromolar activity against a panel of four bacteria. Optimal inhibition was observed when the biscationic amphiphiles possessed modest asymmetry and were composed of between 20 and 24 total carbon atoms in the side chains. These amphiphiles were prepared in a simple two-step procedure, utilizing inexpensive materials and atom-economical reactions, making them practical for further development.

Biofilm-Eradicating Properties of Quaternary Ammonium Amphiphiles: Simple Mimics of Antimicrobial Peptides

Co-reporter:Megan C. Jennings;Laura E. Ator;Thomas J. Paniak; Dr. Kevin P. C. Minbiole; Dr. William M. Wuest

ChemBioChem 2014 Volume 15( Issue 15) pp:2211-2215

Publication Date(Web):

DOI:10.1002/cbic.201402254

Abstract

Bacterial biofilms are difficult to eradicate because of reduced antibiotic sensitivity and altered metabolic processes; thus, the development of new approaches to biofilm eradication is urgently needed. Antimicrobial peptides (AMPs) and quaternary ammonium cations (QACs) are distinct, yet well-known, classes of antibacterial compounds. By mapping the general regions of charge and hydrophobicity of QACs onto AMP structures, we designed a small library of QACs to serve as simple AMP mimics. In order to explore the role that cationic charge plays in biofilm eradication, structures were varied with respect to cationic character, distribution of charge, and alkyl side chain. The reported compounds possess minimum biofilm eradication concentrations (MBEC) as low as 25 μM against Gram-positive biofilms, making them the most active anti-biofilm structures reported to date. These potent AMP mimics were synthesized in 1–2 steps and hint at the minimal structural requirements for biofilm destruction.

The antibacterial activity of 4,4′-bipyridinium amphiphiles with conventional, bicephalic and gemini architectures

Co-reporter:Melissa C. Grenier, Robert W. Davis, Kelsey L. Wilson-Henjum, Jade E. LaDow, Jacob W. Black, Kevin L. Caran, Kyle Seifert, Kevin P.C. Minbiole

Bioorganic & Medicinal Chemistry Letters 2012 Volume 22(Issue 12) pp:4055-4058

Publication Date(Web):15 June 2012

DOI:10.1016/j.bmcl.2012.04.079

Dialkyl 4,4′-bipyridinium compounds are widely employed for their useful redox properties, and are commonly known as viologens due to their intense coloration upon reduction. Despite their prevalence and amphiphilic nature, the antibacterial activity of these compounds remains largely unreported. We have thus prepared a series of mono- and bis-alkylated analogs of 4,4′-bipyridine to investigate structure–activity relationships in their inhibition of a battery of Gram positive and Gram negative bacteria. The prepared cationic compounds were conventional (one cationic head, one non-polar tail), bicephalic (two heads, one tail), or gemini (two heads, two tails) in their amphiphilic structure. Additionally, an isomeric series of six bis-alkylated compounds ranging from symmetric (PQ-11,11) to highly asymmetric (PQ-20,2) were prepared. Four themes of bioactivity emerged: (1) the most bioactive compounds were gemini in structure; (2) 22 carbons in the alkyl chains, with little to modest asymmetry, led to optimal activity; (3) bicephalic compounds were generally comparable to conventional amphiphiles, though only about 12 carbons in the alkyl chains were solubilized in water by each cationic nitrogen; (4) the effects of counterion identity were not evident between chlorides and bromides; however, the presence of the iodide counterion inhibited dissolution in all compounds tested. Three isomeric compounds with little to no asymmetry in tail length, PQ-11,11, PQ-12,10, and PQ-14,8, prepared as the bromide salts, showed comparable and highly potent activity, with MIC levels around 2 μM against 3 of 4 bacteria tested. The simple (one- to two-step) syntheses of potent antimicrobials portend well for future optimization.

Nonlethal amphibian skin swabbing of cutaneous natural products for HPLC fingerprinting

Co-reporter:

Analytical Methods (2009-Present) 2014 - vol. 6(Issue 10) pp:

Publication Date(Web):

DOI:10.1039/C4AY00566J

CAS:1137582-41-2