Global antimicrobial resistance will change the face of modern medicine, and the discovery of novel antimicrobials is one of the many solutions to this challenge. Furthermore, expanding antimicrobial natural product discovery to poorly explored ecological habitats may lead to the identification of novel compounds. In this body of work, deep-sea sponges are investigated as a source for bacterially derived antibiotics. Both cultivation dependent and independent strategies were employed to isolate and identify promising bacterial candidates, in addition to further understanding the sponge host microbiome. Pheronema carpenteri was identified during cultivation efforts as a sponge from which multiple active bacterial strains can be cultivated. The first microbiome of P. carpenteri from two aggregations is reported herein. It was observed that P. carpenteri contains a bacterial community similar to those previously reported for Hexactinellid sponges and that intra- and inter-aggregation distinction occur. To establish methodologies for assessing bioactive compounds purified from bacterial isoaltes, the use of Galleria mellonella larvae were explored as a rapid and scalable in vivo model. Larval weight is demonstrated as a vital parameter to control variability of data when working with pet-food grade larvae. Methodological consideration from working with G. mellonella larvae are then applied to the bioactive compound isoaltes from the strain Delftia acidovorans PB091. PB091 was isolated from P. carpenteri and demonstrated activity against both methicillin resistant Staphylococcus aureus (MRSA) and Escherichia coli. Purification of an active compound was achieved, but it displayed only anti-Gram-positive activity, and was identified as delftibactin A. PB091_S70 delftibactin A demonstrated low levels of in vivo toxicity and a MIC of 25 µg/ml against multiple strains of MRSA. In this body of work, P. carpenteri sponges are reported as promising organisms for both cultivation dependent and independent investigations for natural product discovery. Metagenomic work here was limited, and future work should build upon early data presented here. Deep-sea sponges continue to be an exciting reservoir of bacterially derived natural products, which may aid in tackling AMR.

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