Inhibition of Virulence Gene Expression in Staphylococcus aureus by Novel Depsipeptides from a Marine Photobacterium

Abstract

During a global research expedition, more than five hundred marine bacterial strains capable of inhibiting the growth of pathogenic bacteria were collected. The purpose of the present study was to determine if these marine bacteria are also a source of compounds that interfere with the agr quorum sensing system that controls virulence gene expression in Staphylococcus aureus. Using a gene reporter fusion bioassay, we recorded agr interference as enhanced expression of spa, encoding Protein A, concomitantly with reduced expression of hla, encoding α-hemolysin, and rnaIII encoding RNAIII, the effector molecule of agr. A marine Photobacterium produced compounds interfering with agr in S. aureus strain 8325-4, and bioassay-guided fractionation of crude extracts led to the isolation of two novel cyclodepsipeptides, designated solonamide A and B. Northern blot analysis confirmed the agr interfering activity of pure solonamides in both S. aureus strain 8325-4 and the highly virulent, community-acquired strain USA300 (CA-MRSA). To our knowledge, this is the first report of inhibitors of the agr system by a marine bacterium.

Regulation of Virulence in Staphylococcus aureus : Molecular Mechanisms and Remaining Puzzles

“…Nonetheless, some of these inhibitors share astonishing structural similarity to the native AIP architecture, despite their disparate origin. For instance, solonamides, cochinmicin and avellanin, identified from marine bacteria, actinomycetes and sponges, respectively, each possesses a 16-membered macrocycle and are therefore believed to function through competitive inhibition of AgrC (Figure 7B) (Desouky et al, 2015; Igarashi et al, 2015; Mansson et al, 2011). Two other natural products, 3-oxo-C12-HSL and 4-hydroxy-2-heptylquinoline N-oxide (HQNO) originating from Pseudomonas aeruginosa , are capable of quenching S. aureus autoinduction with a low-micromolar IC 50 (Figure 7C) (Gordon et al, 2013).…”

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

“…Intriguingly, these compounds were also found to inhibit inflammation responses in activated macrophages, reminiscent of the inhibitory activity that 3OC12HSL exhibits on the NF-B pathway (297), which helps to emphasize that bioactive small molecules are capable of targeting several seemingly unrelated pathways. In another study, two novel cyclic depsipeptides were isolated from a marine Photobacterium species and termed solonomides A and B (Table 3); they were identified by screening inhibitory effects against the Staphylococcus aureus agr signaling pathway (141). The four amino acid ring structures, linked via 3-hydroxyoctanoic or 3-hydroxyhexanoic fatty acids, closely resemble the structures of the Agr AIP peptides and would seemingly compete with AIPs in binding to AgrC.…”

Distinct Bacterial Microbiomes Associate with the Deep-Sea Coral Eguchipsammia fistula from the Red Sea and from Aquaria Settings

“…OTU0003 (P. angustum, previously Vibrio angustum/fischeri) was previously described as a squid endosymbiont and closely related taxa are shown to inhibit virulence gene expression (Thompson et al, 2009;Mansson et al, 2011), at least hypothetically indicating functional importance and a potential to form a symbiotic relationship with a metazoan host as suggested by Hernandez-Agreda et al (2016). OTU0086 (P. puraquae) has been identified as a coral-derived endophytic bacterium (Deng et al, 2015).…”