Design and Testing of Safer, More Effective Preservatives for Consumer Products

Buckley, Heather L.; Hart‐Cooper, William M.; Kim, Jong H.; Faulkner, David; Cheng, Luisa W.; Chan, Kathleen L.; Vulpe, Chris D.; Orts, William J.; Amrose, Susan; Mulvihill, Martin J.

doi:10.1021/acssuschemeng.7b00374

Cited by 23 publications

(22 citation statements)

References 114 publications

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“…OG, an alkyl derivative of the natural product gallic acid, was also included in this chemosensitization test as a reference phenolic compound. OG is classified as a GRAS food additive [ 16 ], and is recently determined as a safer, more effective preservative for consumer products [ 35 ]. OG was previously shown to negatively affect the growth of cell wall MAPK mutants [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

Cinnamic Acid Analogs as Intervention Catalysts for Overcoming Antifungal Tolerance

2017

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Disruption of fungal cell wall should be an effective intervention strategy. However, the cell wall-disrupting echinocandin drugs, such as caspofungin (CAS), cannot exterminate filamentous fungal pathogens during treatment. For potency improvement of cell wall-disrupting agents (CAS, octyl gallate (OG)), antifungal efficacy of thirty-three cinnamic acid derivatives was investigated against Saccharomyces cerevisiae slt2Δ, bck1Δ, mutants of the mitogen-activated protein kinase (MAPK), and MAPK kinase kinase, respectively, in cell wall integrity system, and glr1Δ, mutant of CAS-responsive glutathione reductase. Cell wall mutants were highly susceptible to four cinnamic acids (4-chloro-α-methyl-, 4-methoxy-, 4-methyl-, 3-methylcinnamic acids), where 4-chloro-α-methyl- and 4-methylcinnamic acids possessed the highest activity. Structure-activity relationship revealed that 4-methylcinnamic acid, the deoxygenated structure of 4-methoxycinnamic acid, overcame tolerance of glr1Δ to 4-methoxycinnamic acid, indicating the significance of para substitution of methyl moiety for effective fungal control. The potential of compounds as chemosensitizers (intervention catalysts) to cell wall disruptants (viz., 4-chloro-α-methyl- or 4-methylcinnamic acids + CAS or OG) was assessed according to Clinical Laboratory Standards Institute M38-A. Synergistic chemosensitization greatly lowers minimum inhibitory concentrations of the co-administered drug/agents. 4-Chloro-α-methylcinnamic acid further overcame fludioxonil tolerance of Aspergillus fumigatus antioxidant MAPK mutants (sakAΔ, mpkCΔ). Collectively, 4-chloro-α-methyl- and 4-methylcinnamic acids possess chemosensitizing capability to augment antifungal efficacy of conventional drug/agents, thus could be developed as target-based (i.e., cell wall disruption) intervention catalysts.

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Section: Resultsmentioning

confidence: 99%

Cinnamic Acid Analogs as Intervention Catalysts for Overcoming Antifungal Tolerance

2017

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“…antioxidant system, OG also negatively affected cell wall-integrity system of fungi (Kim et al, 2014), which was determined via the inhibition of S. cerevisiae cell wall-integrity MAPK pathway mutants, (4) Antimicrobial activity of alkyl gallates has been quantified against Aspergillus brasiliensis (mold) and also Pseudomonas aeruginosa (Gram negative bacterium) with a hazard assessment (Buckley et al, 2017). OG was determined to possess better antimicrobial activity with lower hazards, when compared to other alkyl derivatives or conventional preservatives (Buckley et al, 2017), (5) Meanwhile, in a separate study, dodecyl gallate (DG) was determined as the most effective alkyl gallate for control of the yeast pathogen C. albicans (Singulani et al, 2017), where GA and DG were the least toxic compounds comparing to other derivatives (Zebrafish embryo model).…”

Section: Introduction (Continued)mentioning

confidence: 99%

Repurposing Common Food Additives (Benzo Derivatives) As New Anti-parasitic Agents

Land

Kim

Huang

et al. 2019

Proceedings of 5th International Electronic Conference on Medicinal Chemistry

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This study examined the anti-protozoal effects of selected benzo derivatives, namely ten gallic acid (GA) alkyl esters (viz., benzoic acid analogs) and twenty-three benzaldehyde analogs, against six different anaerobic human protozoal pathogens-Trichomonas vaginalis, Tritrichomonas foetus, Tritrichomonas foetus-like, Giardia lamblia, Entamoeba histolytica, and Naegleria fowleri. The efficacy of benzaldehyde and gallate (3,4,5-trihydroxybenzoic acid) analogs were investigated in two respects: (1) changing types of side chains and their positions on the benzaldehyde ring [structure-activity relationships (SAR)]; and, (2) changing lengths of alkyl chains esterified with the carboxyl group on gallate. Results of parasite growth inhibition assays indicated that benzo derivatives could be further developed as potent anti-protozoal drug candidates/leads, where GA having longer alkyl chains exhibited higher anti-protozoal activity than compounds with shorter alkyl chains or all benzaldehyde analogs tested. The chemical libraries were also screened against common human microbiome bacteria and no detectable inhibition was observed. Structure-activity relationships and their implications for new drug discovery against these sexually-transmitted, water-borne, and foodborne parasites are discussed.

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“…OG, an alkyl derivative of the natural product gallic acid (Figure 1), was investigated as a potent chemosensitizer (intervention catalyst) to enhance the efficacy of cell wall-disrupting drug CAS. We recently determined that OG functioned as a safer, more effective preservative for consumer products [9]. [4,7] and the references therein).…”

Section: Introductionmentioning

confidence: 99%

Octyl Gallate as an Intervention Catalyst to Augment Antifungal Efficacy of Caspofungin

Kim¹,

Chan²,

Cheng³

2018

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Filamentous fungi such as Aspergillus spp. are opportunistic pathogens, which cause highly invasive infections, especially in immunocompromised individuals. Control of such fungal pathogens is increasingly problematic due to the small number of effective drugs available for treatment. Moreover, the increased incidence of fungal resistance to antifungal agents makes this problem a global human health issue. The cell wall integrity system of fungi is the target of antimycotic drugs echinocandins, such as caspofungin (CAS). However, echinocandins cannot completely inhibit the growth of filamentous fungal pathogens, which results in survival/escape of fungi during treatment. Chemosensitization was developed as an alternative intervention strategy, where co-application of CAS with the intervention catalyst octyl gallate (OG; chemosensitizer) greatly enhanced CAS efficacy, thus achieved ≥99.9% elimination of filamentous fungi in vitro. Based on hypersensitive responses of Aspergillus antioxidant mutants to OG, it is hypothesized that, besides destabilizing cell wall integrity, the redox-active characteristic of OG may further debilitate the fungal antioxidant system.

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Design and Testing of Safer, More Effective Preservatives for Consumer Products

Cited by 23 publications

References 114 publications

Cinnamic Acid Analogs as Intervention Catalysts for Overcoming Antifungal Tolerance

Cinnamic Acid Analogs as Intervention Catalysts for Overcoming Antifungal Tolerance

Repurposing Common Food Additives (Benzo Derivatives) As New Anti-parasitic Agents

Octyl Gallate as an Intervention Catalyst to Augment Antifungal Efficacy of Caspofungin

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