Terrestrial actinomycetes in the genus Streptomyces have long been recognized as prolific producers of small-molecule natural products, including many clinically important antibiotics and cytotoxic agents. Although Streptomyces can also be isolated from marine environments, their potential for natural product biosynthesis remains underexplored. The MAR4 clade of largely marine-derived Streptomyces has been a rich source of novel halogenated natural products of diverse structural classes. To further explore the biosynthetic potential of this group, we applied pattern-based genome mining, leading to the discovery of the first halogenated pyrroloketoindane natural products, indanopyrrole A (1) and B (2), and the bioinformatic linkage of these compounds to an orphan biosynthetic gene cluster (BCG) in 20 MAR4 genomes. Indanopyrrole A displays potent broad-spectrum antibiotic activity against clinically relevant pathogens. A comparison of the putative indanopyrrole BGC with that of the related compound indanomycin provides new insights into the terminal cyclization and offloading mechanisms in pyrroloketoindane biosynthesis. Broader searches of public databases reveal the rarity of this BGC while also highlighting opportunities for discovering additional compounds in this uncommon class.

The tropical marine cyanobacterium Moorena producens JHB is a prolific source of secondary metabolites with potential biomedical utility. Previous studies on this strain led to the discovery of several novel compounds such as hectochlorins and jamaicamides. However, bioinformatic analyses of its genome indicate the presence of numerous cryptic biosynthetic gene clusters that have yet to be characterized. To potentially stimulate the production of novel compounds from this strain, it was cocultured with Candida albicans. From this experiment, we observed the increased production of a new compound that we characterize here as hectoramide B. Bioinformatic analysis of the M. producens JHB genome enabled the identification of a putative biosynthetic gene cluster responsible for hectoramide B biosynthesis. This work demonstrates that coculture competition experiments can be a valuable method to facilitate the discovery of novel natural products from cyanobacteria.

Klebsiella pneumoniae (Kp) is a leading cause of hospital- and community-acquired infections and is increasingly resistant to last-line antibiotics, positioning it as a World Health Organization-designated priority pathogen. Vaccine development has been hindered by the extensive diversity of Kp exopolysaccharide capsules. We developed a cellular nanoparticle (CNP) platform in which bacterial outer membrane vesicles (OMVs) are stably coated onto a STING (stimulator of interferon genes)-adjuvanted nanoparticle core (CNP-KpSTING). The resulting ∼100-nm nanoparticles are homogenous and optimized for recruitment and activation of antigen-presenting cells in draining lymph nodes. CNP-KpSTING vaccination elicited robust antibody responses, enhanced neutrophil-mediated bacterial clearance, and conferred cross-protection against heterologous Kp capsule types in vitro and in lethal pneumonia models. Passive transfer of post-vaccination sera reduced bacterial burden and inflammatory cytokines in the lungs of infected mice. These findings establish CNP-KpSTING as a versatile platform that addresses key antigenic barriers inherent to Kp and support OMV-CNPs as a promising foundation for broadly protective vaccines against multidrug-resistant Gram-negative pathogens.

Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli are a major antimicrobial resistance threat. Although not standard therapy, azithromycin (AZM) displayed potent activity against ESBL E. coli in vitro, ex vivo, and in vivo. AZM demonstrated multi-fold reductions in MIC, bactericidal activity in supplemented mammalian tissue culture media, and enhanced dose-dependent activity with sodium bicarbonate (NaHCO3). AZM also augmented complement-mediated killing in human serum and improved survival by 50% in a murine bloodstream infection model. These findings underscore the need to revisit antibiotic susceptibility testing—incorporating host defense factors and NaHCO3—and suggest AZM merits further clinical evaluation for ESBL E. coli infections.

Urinary tract infections (UTIs) are common in children and are predominantly caused by uropathogenic Escherichia coli (UPEC). An increasing proportion of these strains produce extended-spectrum β-lactamases (ESBLs), which render β-lactam antibiotics ineffective. Interestingly, some patients with ESBL-producing UTIs improve clinically following treatment with antibiotics like cephalexin, despite demonstrated in vitro resistance. Working alongside and at times synergistically with antibiotics, host immune factors, such as the antimicrobial peptide cathelicidin (LL-37), contribute to bacterial clearance through direct killing and inhibition of biofilm formation. In this review, we summarize the current understanding of pediatric ESBL-producing UPEC infections and present selected in vitro and in vivo experimental data evaluating the combined effects of LL-37 and cephalexin on clinical isolates. Although no synergy was observed, ESBL-producing isolates demonstrated reduced bacterial burden in vivo compared to a non-ESBL UPEC strain. These findings suggest that host immune factors and environmental conditions may influence the fitness and virulence of drug-resistant UTI pathogens, warranting further investigation.