作者: Sweeney, Taylor R. ; Haag, Anthony M. ; Haidacher, Sigmund J. ; Shin, Ronald ; Glogauer, Michael ; Williams, McKinley D. ; Hansanant, Nopakorn ; Orugunty, Ravi ; Tenorio, Abraham ; Barbour, Abdelahhad ; Horvath, Thomas D. ; Younesi, Fereshteh ; Smith, Leif ; Trieu, Sabrina ; Cao, Kevin ; Lu, Shi-En

ABSTRACT:

Biofilms are an important colonization mechanism employed by several microbial species to better establish themselves and monopolize the acquisition of resources across different environs. Some bacteria have evolved specialized metabolites that, when secreted, disrupt the formation and stability of biofilms generated by competing heterospecies, providing the producing organism with an ecological advantage. Soil-derived species are probable candidates for the identification of such compounds, given the intense level of competition that occurs within the terrestrial ecosystem. The MS14 strain of Burkholderia contaminans isolated from soil in Mississippi has previously been shown to produce antimicrobial compounds like occidiofungin and ornibactin. In this report, we demonstrate that this strain also produces 4-hydroxy-3-methyl-2-alkenylquinoline (HMAQ-7), an alkaloid-based metabolite structurally similar to others produced by Burkholderia . HMAQ-7 was isolated and purified in sufficient quantities to enable the elucidation of its covalent structure and the evaluation of its biological effects. The compound was found to possess a unique ability to inhibit biofilm biosynthesis in several species, including opportunistic pathogens like Staphylococcus haemolyticus and within saliva-derived multispecies biofilms. HMAQ-7 also demonstrated an ability to modulate additional cellular behaviors in Bacillus subtilis, including motility and sporulation, suggesting that this molecule is important to the interspecies dynamics present across many diverse microenvironments.

IMPORTANCE:

The present study furthers our understanding of the structural complexity and the biological functions of the 2-alkyl-4(1H)-quinolone metabolites produced by Burkholderia spp. Low micromolar concentrations of HMAQ-7′ induced observable bacterial growth morphology differences. The antibiofilm properties of the HMAQ-7′ characterized in this study will promote future investigations into possible biological and applied roles. The ability to alter biofilm formation using HMAQ-7′ may facilitate Burkholderia spp. colonization in a multitude of environments, that is, aquatic, soil, and possibly during infection. HMAQ may subvert competition by potential competitor species in natural environments of Burkholderia spp. and possibly lung infections of cystic fibrosis patients.

2025-04-01·JOURNAL OF MASS SPECTROMETRY

Development of an LC–MS/MS Method for Quantifying Occidiofungin in Rabbit Plasma

Article

作者: Cothrell, Andrew ; Orugunty, Ravi S. ; Smith, Leif

ABSTRACT:

Fungal infections are caused by opportunistic pathogens that can be life threatening and have been growing in prevalence. Many clinically relevant pathogens have resistance to or are developing resistance to the commonly used antifungal treatments. Occidiofungin (OCF) is a unique cyclic lipoglycopeptide with a novel structure that includes noncanonical amino acid in its covalent structure. It exhibits broad spectrum antifungal activity and has activity against drug resistant Candida species. Occidiofungin is a fungicidal compound that has a novel mechanism of action in which it disrupts higher order actin structures. Currently, occidiofungin is being developed for use in treating vulvovaginal candidiasis (VVC) and recurrent vulvovaginal candidiasis (RVVC). This study describes the development and application of a bioanalytical method for the quantification of occidiofungin in rabbit plasma. Method development was performed to quantify occidiofungin in rabbit plasma after intravaginal administration of a hydrogel containing occidiofungin. The method was validated with a linear range of 30–15 000 ng/mL in rabbit plasma. Precision, accuracy, calibration curve linearity, and stability of drug in plasma were established in quality controls. Extract stability, matrix effects, and recovery of drug in the extract were also determined. This study supported a repeat dose toxicity study in rabbits to determine occidiofungin pharmacokinetics and toxicokinetics. The pharmacokinetic and toxicokinetic primarily showed plasma concentrations of occidiofungin below the limit of quantification (BLOQ), suggesting that OCF‐B does not readily cross the vaginal epithelial membrane.

2024-02-23·Journal of natural products

Previously Uncharacterized Variants, OCF-E–OCF-J, of the Antifungal Occidiofungin Produced by Burkholderia contaminans MS14

Article

作者: Cao, Kevin ; Smith, Leif ; Hansanant, Nopakorn ; Cothrell, Andrew ; Ju, Min ; Tenorio, Abraham ; Buhrow, Andrew R ; Shin, Ronald ; Orugunty, Ravi ; Kummari, Evangel ; McNally, Noah ; Williams, McKinley ; Joseph, Thushinari

The rise of multidrug resistant fungal infections highlights the need to identify and develop novel antifungal agents. Occidiofungin is a nonribosomally synthesized glycolipopeptide that has a unique mechanism of action, disrupting actin-mediated functions and inducing cellular apoptosis. Antifungal activity has been observed in vitro against various fungal species, including multidrug resistant Candida auris, and in vivo efficacy has been demonstrated in a murine vulvovaginal candidiasis model. Occidiofungin, a cyclic glycolipopeptide, is composed of eight amino acids and in previous studies, an asparagine residue was assigned at position 7 (ASN7). In this study, new structural variants of occidiofungin have been characterized which have aspartic acid (ASP7), glutamine (GLN7), or glutamic acid (GLU7) at position 7. The side chain of the ASP7 variant contains the only terminal carboxylic acid in the peptide and provides a useful site for selective chemical modifications. Analogues were synthesized at the ASP7 position and tested for antifungal activity. These analogues were shown to be more active as compared to the ASP7 variant against a panel of Candida species. The naturally occurring variants of occidiofungin with a side chain containing a carboxylic acid at the seventh amino acid position can be used to develop semisynthetic analogues with enhanced therapeutic properties.

100 项与 OCF-001 相关的药物交易

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