Advances in Natural Products from the Marine-Sponge-Associated Microorganisms with Antimicrobial Activity in the Last Decade

**Background:** Marine sponges host diverse microbial communities that produce structurally novel secondary metabolites as a chemical defense mechanism. With antibiotic resistance emerging as a global threat, there is urgent need for new antimicrobial agents. While previous reviews covered limited numbers of antimicrobial compounds from sponge-associated microorganisms, this review provides a comprehensive overview of 270 secondary metabolites reported between 2012 and 2022.

**Methods:** The authors conducted a literature survey of studies published from 2012 to 2022 reporting secondary metabolites isolated from sponge-associated microorganisms with antimicrobial activity. Compounds were categorized by source organism (fungi, actinomycetes, other bacteria, or co-culture methods), structural class, and antimicrobial activity profile. Minimum inhibitory concentration (MIC) values and other activity data were extracted directly from the original publications.

**Key Results:** Of the 270 secondary metabolites reviewed, 68.5% were derived from fungi, 23.3% from actinomycetes, 3.7% from other bacteria, and 4.4% were discovered using co-culture methods. The dominant fungal genera included Aspergillus, Penicillium, and Fusarium. Structurally, the compounds comprised polyketides (51.9%), alkaloids (17.4%), terpenoids (13%), peptides (11.5%), and glucosides (3.3%). Among the 270 compounds, 124 were new compounds and 146 were known compounds, with 55 exhibiting antifungal activity in addition to antibacterial effects. Notable compounds with potent activity included: diaporthalasin (10) with MIC of 2 µg/mL against both S. aureus and MRSA; austalide R (11) and austalide M (12) with broad-spectrum MIC values of 0.001–10 µg/mL against multiple Vibrio species; citrinin (42) with MIC values of 3.90 µg/mL against MRSA and 0.97 µg/mL against rifampicin-resistant S. aureus; emeguisin A (138) with MIC of 0.5 µg/mL against S. aureus, MRSA, and Cryptococcus neoformans; and kocurin (241) with potent anti-MRSA activity (MIC 0.25–0.5 µg/mL). Several compounds demonstrated activity against multi-drug-resistant strains including MRSA, vancomycin-resistant Enterococcus (VRE), and Mycobacterium tuberculosis. The review also discusses structure-activity relationships, noting for example that the carboxyl group or its methyl ester in certain peptides (compounds 173–174) enhanced antibacterial activity, and that the NO2 sugar and aldehyde group at C-23 were important for activity in tetrocarcin glycosides.

**Clinical Implications:** The reviewed compounds represent promising lead molecules for developing new antibiotics against drug-resistant pathogens. Several compounds showed activity comparable to positive controls: fonsecinone A (116) and isoaurasperone A (117) matched ampicillin sodium activity, while isochaetochromin B2 (40) and ustilaginoidin D (41) showed activity equivalent to streptomycin sulphate against M. phlei. The combination of citrinin (42) with vancomycin improved survival in VRE-infected mice. Physcion (89) demonstrated in vivo efficacy against Chlamydia psittaci comparable to doxycycline. However, the authors note that only a small number of compounds have undergone drug-likeness, pharmacokinetic, and toxicity evaluation, and that further in vivo and preclinical studies are needed. The review emphasizes that new culture strategies (such as co-cultivation and OSMAC approaches) and advanced analytical techniques (including QM-NMR and molecular networking) will be important for discovering additional novel antimicrobial compounds from sponge-associated microorganisms.