A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance.

The rise of antibiotic resistance and declining discovery of new antibiotics has created a global health crisis. Of particular concern, no new antibiotic classes have been approved for treating Gram-negative pathogens in decades. Here, we characterize a compound, SCH-79797, that kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism of action (MoA) with undetectably low resistance frequencies. To characterize its MoA, we combined quantitative imaging, proteomic, genetic, metabolomic, and cell-based assays. This pipeline demonstrates that SCH-79797 has two independent cellular targets, folate metabolism and bacterial membrane integrity, and outperforms combination treatments in killing methicillin-resistant Staphylococcus aureus (MRSA) persisters. Building on the molecular core of SCH-79797, we developed a derivative, Irresistin-16, with increased potency and showed its efficacy against Neisseria gonorrhoeae in a mouse vaginal infection model. This promising antibiotic lead suggests that combining multiple MoAs onto a single chemical scaffold may be an underappreciated approach to targeting challenging bacterial pathogens.

Filling the gap between evidence, policy and practice: are 45 and Up Study researchers planning for impact?

AIM: To improve health outcomes, policy and practice decisions should be guided by relevant and timely evidence. High-quality, large-scale population data could play an essential role in supporting evidence-based decision making. The 45 and Up Study is a long-term, large-scale cohort study with more 250 000 participants aged 45 years and over from New South Wales (NSW), Australia. Data collected by the Study is accessible to researchers, government and non-governmental bodies. The study aimed to identify the proportion of researchers using data from the Study who intended to have an impact and achieved impact; the types of impact they intended and achieved; and the pathways through which they achieved it. METHODS: Using data extracted from the application, progress and final report documents for 25 projects using 45 and Up Study data from January 2011 until December 2017, we a) determined the proportion of projects that intended to have policy or practice impact and b) described the type of policy and practice impact achieved. RESULTS: We found that 88% (n = 22) of projects intended to have a policy or practice impact. Of those, 68% (n = 15) planned to influence or inform a policy or program, and 41% (n = 9) planned to share findings at conferences or in journals. Almost half of projects with intended impact (45%, n = 10) did not state how they planned to achieve impact. Approximately 16% of all projects (n = 4) reported achieving an impact on policy or services. The type of impact achieved by all four of these projects was influencing, informing or changing a policy or program. One of these four projects also achieved a change to legislation or regulation. CONCLUSIONS: Further strategies to promote a targeted approach to impact planning in research projects using datasets such as the 45 and Up Study would help guide researchers in achieving impact.

Both clinical and environmental Caulobacter species are virulent in the Galleria mellonella infection model.

The Caulobacter genus, including the widely-studied model organism Caulobacter crescentus, has been thought to be non-pathogenic and thus proposed as a bioengineering vector for various environmental remediation and medical purposes. However, Caulobacter species have been implicated as the causative agents of several hospital-acquired infections, raising the question of whether these clinical isolates represent an emerging pathogenic species or whether Caulobacters on whole possess previously-unappreciated virulence capability. Given the proposed environmental and medical applications for C. crescentus, understanding the potential pathogenicity of this bacterium is crucial. Consequently, we sequenced a clinical Caulobacter isolate to determine if it has acquired novel virulence determinants. We found that the clinical isolate represents a new species, Caulobacter mirare that, unlike C. crescentus, grows well in standard clinical culture conditions. C. mirare phylogenetically resembles both C. crescentus and the related C. segnis, which was also thought to be non-pathogenic. The similarity to other Caulobacters and lack of obvious pathogenesis markers suggested that C. mirare is not unique amongst Caulobacters and that consequently other Caulobacters may also have the potential to be virulent. We tested this hypothesis by characterizing the ability of Caulobacters to infect the model animal host Galleria mellonella. In this context, two different lab strains of C. crescentus proved to be as pathogenic as C. mirare, while lab strains of E. coli were non-pathogenic. Further characterization showed that Caulobacter pathogenesis in the Galleria model is mediated by lipopolysaccharide (LPS), and that differences in LPS chemical composition across species could explain their differential toxicity. Taken together, our findings suggest that many Caulobacter species can be virulent in specific contexts and highlight the importance of broadening our methods for identifying and characterizing potential pathogens.