The potential of the diverse chemistries present in natural products (NP) for biotechnology and medicine remains untapped because NP databases are not searchable with raw data and the NP community has no way to share data other than in published papers. Although mass spectrometry techniques are well-suited to high-throughput characterization of natural products, there is a pressing need for an infrastructure to enable sharing and curation of data. We present Global Natural Products Social molecular networking (GNPS, http://gnps.ucsd.edu), an open-access knowledge base for community wide organization and sharing of raw, processed or identified tandem mass (MS/MS) spectrometry data. In GNPS crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations. Data-driven social-networking should facilitate identification of spectra and foster collaborations. We also introduce the concept of ‘living data’ through continuous reanalysis of deposited data.

Anthracimycin is a recently discovered novel marine-derived compound with activity against Bacillus anthracis. We tested anthracimycin against an expanded panel of Staphylococcus aureus strains in vitro and in vivo. All strains of S. aureus tested, including methicillin-sensitive (MSSA), methicillin-resistant (MRSA), and vancomycin-resistant strains of S. aureus were sensitive to anthracimycin at minimum inhibitory concentrations (MIC) of < 0.25 mg/L. Although its post-antibiotic effects were minimal, anthracimycin exhibited potent and rapid bactericidal activity, with a > 4-log kill of USA300 MRSA within 3 hours at 5 times its MIC. At concentrations significantly below the MIC, anthracimycin slowed MRSA growth and potentiated the bactericidal activity of the human cathelicidin, LL-37. The bactericidal activity of anthracimycin was somewhat mitigated in the presence of 20% human serum, and the compound was minimally toxic to human cells, with an IC50 = 70 mg/L against human carcinoma cells. At concentrations near the MIC anthracimycin inhibited S. aureus nucleic acid synthesis as determined by optimized macromolecular synthesis methodology, with inhibition of DNA and RNA synthesis occurring in the absence of DNA intercalation. Anthracimycin at a single dose of 1 or 10 mg/kg was able to protect mice from MRSA-induced mortality in a murine peritonitis model of infection. Anthracimycin provides an interesting new scaffold for future development of a novel MRSA antibiotic.

Molecular genetic analysis indicates that the problematic human bacterial pathogen methicillin-resistant Staphylococcus aureus possesses more than 2000 open reading frames in its genome. This number of potential gene products, coupled with intrinsic mechanisms of posttranslational modification, endows methicillin-resistant Staphylococcus aureus with a highly complex biochemical repertoire. Recent proteomic and metabolomic advances have provided methodologies to better understand and characterize the biosynthetic factors released by microbial organisms. Here, the emerging tool of mass spectrometry-based molecular networking was used to visualize and map the repertoire of biosynthetic factors produced by a community-associated methicillin-resistant Staphylococcus aureus strain representative of the epidemic USA300 clone. In particular, the study focused on elucidating the complexity of the recently discovered phenol soluble modulin family of peptides when placed under various antibiotic treatment stresses. Novel PSM truncated variant peptides were captured, and the type of variants that were clustered by the molecular networks platform changed in response to the different antibiotic treatment conditions. After discovery, a group of the peptides were selected for functional analysis in vitro. The peptides displayed bioactive properties including the ability to induce proinflammatory responses in human THP-1 monocytes. Additionally, the tested peptides did not display antimicrobial activity as previously reported for other phenol soluble modulin truncated variants. Our findings reveal that the PSM family of peptides are quite structurally diverse, and suggest a single phenol soluble modulin parent peptide can functionally spawn differential bioactivities in response to various external stimuli. Molecular & Cellular Proteomics

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Background A prior study demonstrated suboptimal antibiotic prescribing in the emergency department (ED) at 77.4% for uncomplicated lower respiratory tract infections (LRTI), urinary tract infections (UTI), and acute bacterial skin and skin structure infections (ABSSSI). This study measured the effect of indication-based antibiotic order sentences (AOS) on prescribing. Methods IRB-approved quasi-experiment of adults prescribed antibiotics in ED for uncomplicated LRTI, UTI, or ABSSSI from January - June 2019 (pre-group) or September - December 2021 (post-group). Exclusion: hospital admission, immunocompromised, active cancer, or prophylactic antibiotics. AOS are lean process, electronic discharge prescriptions retrievable by name or indication; AOS implementation occurred July 2021. Optimal prescribing was defined as the correct antibiotic selection, dose, and duration per local and national guidelines. Seven-day endpoints: antibiotic escalation, ED or hospital readmission, any outpatient contact, and reported adverse drug event (ADE). Descriptive and bivariate statistics performed. Variables considered for multivariable logistic regression had p&lt; 0.2 or plausible association with optimal prescribing. Results 294 patients included: 147-pre and 147-post. Patient characteristics are in Table 1. Overall optimal prescribing improved from 12 (8.2%) to 34 (23.1%) (p&lt; 0.001). Breakdown of optimal prescribing in pre- and post-groups: selection 90 (61.2%) vs 117 (79.6%) (p&lt; 0.001), dose 99 (67.3%) vs 115 (78.2%) (p=0.036), duration 38 (25.9%) vs 50 (34%) (p=0.126). After adjustment, AOS were independently associated with optimal prescribing (Table 2). Secondary endpoints: antibiotic escalation 10 (6.8%) vs 7 (4.8%) (p=0.662), hospital or ED readmission 12 (8.2%) vs 10 (6.8%) (p=0.658), outpatient contact 31 (21.1%) vs 28 (19%) (p=0.662), and ADE 2 (1.4%) vs 4 (2.7%) (p=0.684). Post-hoc analysis showed suboptimal uptake of AOS by ED prescribers. Table 1:Baseline and Clinical CharacteristicsTable 2:Bivariable and Multivariable Regression Analysis of Factors Associated with Optimal Prescribing†Covaries with intervention group; Hosmer and Lemeshow p = 0.68; Method: backwards logistic regression; No variables removed Conclusion AOS is an efficient and promising antimicrobial stewardship strategy; provider re-education is needed to increase AOS uptake. Disclosures All Authors: No reported disclosures.