Antibiotic resistance has rendered many conventional antibiotics obsolete and contributed to the deaths of 1.2 million people in 2019. The ESKAPE pathogens-Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter sp.-pose the largest challenges as they contain multiple resistance mechanisms, surviving up to 10-1000-fold the normal doses of antibiotics. In addition, several ESKAPE pathogens actively evade antibiotics by forming protective barriers known as biofilms. Biofilms, surface-adhered multicellular communities of bacteria, are enclosed in a matrix of extracellular polymeric substances. Bacteria within biofilms can also tolerate up to 1000-fold the normal dose of antibiotics. Biofilm infections contribute to approximately 80% of all chronic bacterial infections, with ESKAPE-pathogen biofilm-infections posing a significant challenge with current antibiotic therapies. Although an obvious need exists for small molecule therapeutics targeting biofilm infections, the FDA has approved none. Efforts to directly target biofilms with small molecules have focused on developing therapeutics that disrupt biofilm formation or eradicate already formed biofilms. These therapeutics would be used in conjunction with traditional antibiotics to eliminate the infection completely. However, in recent years, several natural products have been shown to possess the desired activity in either in vitro or in vivo assays (Fig. ). A couple examples include auromomycin (1), which is produced by a marine sediment bacterium and possess strong biofilm formation inhibition (IC50 60.1 μM) against Vibrio cholerae. A subsequent structure activity relationship (SAR) study led to a related oxazine (2) that is 10-fold more potent (IC50 6 μM) while also possessing biofilm disruption properties. In addition, two marine sponges, Agelas conifera and A. oroides, produce bromoageliferin (3) and oroidin (4), bromopyrrole alkaloids that inhibit biofilm formation in methicillin-resistant S. aureus (MRSA) and A. baumannii. Finally, streptorubin B (5), produced by multiple Streptomyces strains, inhibits at least 70% biofilm formation in S. aureus at about 1 μg/mL. The mechanism of action (MOA) of many biofilm inhibitors/disruptors is unknown. However, several hypotheses abound, including disruption of quorum sensing, chelating iron, or targeting the cdi-GMP signaling pathway. Innate substrates in the marine environment become micro-biofouled, accumulating microorganisms on wet surfaces, along with many living substrates, such as mangrove roots and sea grass. Micro-biofouling is mechanistically similar to forming biofilms in humans. Interestingly, some marine organisms appear to resist biofouling; these organisms can be leveraged as a source of potential antibiofilm metabolites. One particular source is marine egg masses or clutches. Many marine organisms lay egg masses that are unprotected, i.e. no hard external shell or parental protection, yet, they do not appear to experience biofouling. This includes egg masses of the Hawaiian Bobtail Squid, moon snails, and nudibranchs. Researchers propose that the microbiota of egg masses has a role in preventing microbial fouling, as treatment with antibiotics prior to microbial challenge experiments renders the egg masses more sensitive to infection.