Zinc Chelation by a Small-Molecule Adjuvant Potentiates Meropenem Activity in Vivo against NDM-1-Producing Klebsiella pneumoniae

The widespread emergence of antibiotic drug resistance has resulted in a worldwide healthcare crisis. In particular, the extensive use of β-lactams, a highly effective class of antibiotics, has been a driver for pervasive β-lactam resistance. Among the most important resistance determinants are the metallo-β-lactamases (MBL), which are zinc-requiring enzymes that inactivate nearly all classes of β-lactams, including the last-resort carbapenem antibiotics. The urgent need for new compounds targeting MBL resistance mechanisms has been widely acknowledged; however, the development of certain types of compoundsnamely metal chelatorsis actively avoided due to host toxicity concerns. The work herein reports the identification of a series of zinc-selective spiro-indoline-thiadiazole analogues that, in vitro, potentiate β-lactam antibiotics against an MBL-carrying pathogen by withholding zinc availability. This study demonstrates the ability of one such analogue to inhibit NDM-1 in vitro and, using a mouse model of infection, shows that combination treatment of the respective analogue with meropenem results in a significant decrease in bacterial burden in contrast to animals that received antibiotic treatment alone. These results support the therapeutic potential of these chelators in overcoming antibiotic resistance

Pharmacological Characterization of A-i 27722: An Orally Active and Highly Potent ETA-Selective Receptor Antagonist

ABSTRACT Endothelins (ET) are potent vasoactive peptides implicated i

Adapting tropical Pacific fisheries and aquaculture to\ud climate change: management measures, policies and investments

This chapter sets out the information needed by stakeholders in the fisheries and aquaculture sector at all levels to reduce the threats and capitalise on the\ud opportunities created by climate change. In particular, we:\ud \ud outline the existing management regimes and initiatives for industrial and smallscale fisheries and aquaculture in the region to secure desired human development outcomes and maintain healthy fish stocks; \ud \ud identify an appropriate framework for selecting practical adaptations to address the key near-term drivers for fisheries and aquaculture, and the future effects of climate change; recommend adaptations, and suggest policy approaches, to maximise the contributions of fisheries and aquaculture to economic development, government revenue, food security and livelihoods as the climate changes; outline the value of modelling to examine interactions among adaptation options; \ud \ud explain the need to monitor the projected effects of climate change on the sector; summarise the gaps in knowledge to be filled to improve understanding of the\ud vulnerability of fisheries and aquaculture in the tropical Pacific to climate change, and to fine-tune key adaptations;\ud \ud identify priority investments needed to apply the main adaptations, fill gaps in knowledge, strengthen partnerships, monitor the projected effects of climate\ud change and measure the success of adaptations; \ud \ud and consider sources of funding to make the necessary investments.\ud \ud We emphasise that adaptations and policies to build the resilience of the Pacific communities to climate change should not be viewed just from a scientific or technical perspective – the needs and aspirations of people must also be integrated. Understanding how people are affected, and how their traditional knowledge, capacities and perspectives can help develop and implement adaptations is a vital part of the process. Communityii consultation and participation are essential to ensure that adaptations incorporate a human rights and human development approach\ud to achieve gender equality, maintain relevant traditional customs and culture, and empower young people

2018 international consensus meeting on musculoskeletal infection: Research priorities from the general assembly questions

Musculoskeletal infections (MSKI) remain the bane of orthopedic surgery, and result in grievous illness and inordinate costs that threaten healthcare systems. As prevention, diagnosis, and treatment has remained largely unchanged over the last 50 years, a 2nd International Consensus Meeting on Musculoskeletal Infection (ICM 2018, https://icmphilly.com) was completed. Questions pertaining to all areas of MSKI were extensively researched to prepare recommendations, which were discussed and voted on by the delegates using the Delphi methodology. The questions, including the General Assembly (GA) results, have been published (GA questions). However, as critical outcomes include: (i) incidence and cost data that substantiate the problems, and (ii) establishment of research priorities; an ICM 2018 research workgroup (RW) was assembled to accomplish these tasks. Here, we present the result of the RW consensus on the current and projected incidence of infection, and the costs per patient, for all orthopedic subspecialties, which range from 0.1% to 30%, and $17,000 to$150,000. The RW also identified the most important research questions. The Delphi methodology was utilized to initially derive four objective criteria to define a subset of the 164 GA questions that are high priority for future research. Thirty-eight questions (23% of all GA questions) achieved the requisite &gt; 70% agreement vote, and are highlighted in this Consensus article within six thematic categories: acute versus chronic infection, host immunity, antibiotics, diagnosis, research caveats, and modifiable factors. Finally, the RW emphasizes that without appropriate funding to address these high priority research questions, a 3rd ICM on MSKI to address similar issues at greater cost is inevitable.</p