Date of Award

Spring 5-2026

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Pharmaceutical Sciences

First Advisor

Sherif Elshahawi

Second Advisor

Keykavous Parang

Third Advisor

Innokentiy Maslennikov

Abstract

Antimicrobial resistance (AMR) has been an ongoing global emergency since 2015, when the World Health Organization (WHO) first declared it a global emergency. In 2021, AMR was directly responsible for 1.14 million deaths, and projections estimate this death count could rise to 10 million by 2050. Notably, Gram-negative bacteria account for the majority of alerts due to their intrinsic multidrug resistance mechanisms, impermeable outer membranes, and rapid acquisition of additional resistance genes. To address the urgent need for novel antibiotics, we considered exploiting natural products (NPs) produced by soil microorganisms. NPs are of major significance for antibacterial compounds, with 55% of approved antibacterials from 1981 to 2019 derived or inspired by NPs. NPs continue to serve as major sources of novel bioactive compounds and scaffolds with substantial unexplored biosynthetic diversity remaining in nature. Soil samples collected from unexplored areas, such as Death Valley and Joshua Tree National Parks, were used to create a library of >900 pure microbial strains. All microbial strains were grown on a small scale and screened for anti-Gram-negative activity. Moreover, the liquid chromatography-mass spectrometry profiles were obtained. The combined data were used to prioritize a list of strains for further assessment of their metabolite profiles using large-scale fermentation. A single strain was then fermented on a large scale, and, through bioassay-guided fractionation using different chromatography methods, the main compound responsible for activity was purified. Using high-

resolution mass spectrometry, and 1- and 2-dimensional nuclear magnetic resonance spectroscopy, the structure of the bioactive compound was elucidated. The minimum inhibitory concentration (MIC) of the compound was found to be from 0.0625 – 1 μg/mL against a panel of Gram-negative bacteria and showed minimal cytotoxicity up to 160 μM. Moreover, a methylated derivative of this compound was purified and structurally elucidated but showed no activity against the same panel at its tested concentration. This study highlights the potential of underexplored microbial sources for the discovery of antibiotics to combat AMR.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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