In Vivo Activity Profiling of Biosynthetic Darobactin D22 against Critical Gram-Negative Pathogens.

In recent years, naturally occurring darobactins have emerged as a promising compound class to combat infections caused by critical Gram-negative pathogens. In this study, we describe the in vivo evaluation of derivative D22, a non-natural biosynthetic darobactin analogue with significantly improved antibacterial activity. We found D22 to be active in vivo against key critical Gram-negative human pathogens, as demonstrated in murine models of thigh infection, peritonitis/sepsis, and urinary tract infection (UTI).

Thermo-amplifier circuit in probiotic E. coli for stringently temperature-controlled release of a novel antibiotic.

Peptide drugs have seen rapid advancement in biopharmaceutical development, with over 80 candidates approved globally. Despite their therapeutic potential, the clinical translation of peptide drugs is hampered by challenges in production yields and stability. Engineered bacterial therapeutics is a unique approach being explored to overcome these issues by using bacteria to produce and deliver therapeutic compounds at the body site of use.

Structure Revision of Halisphingosine A via Total Synthesis and Bioactivity Studies.

Sphingoid bases are important bioactive lipids found in a variety of organisms, serving as the backbone of sphingolipids, which regulate essential physiological processes. Here we describe the total synthesis and structure revision of halisphingosine A, a sphingoid base initially isolated from marine sponges. To address inconsistencies in the NMR interpretation of this natural product, we developed a synthetic route involving a late-stage enantioselective Henry reaction that allows access to multiple stereoisomers of the proposed halisphingosine A core structure.

Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity.

In a fragment-based approach using NMR spectroscopy, benzyloxyacetohydroxamic acid-derived inhibitors of the bacterial deacetylase LpxC bearing a substituent to target the uridine diphosphate-binding site of the enzyme were developed. By appending privileged fragments via a suitable linker, potent LpxC inhibitors with promising antibacterial activities could be obtained, like the one-digit nanomolar LpxC inhibitor ()- [ (LpxC C63A) = 9.5 nM; (LpxC): 5.

Targeting IspD in the Methyl-d-erythritol Phosphate Pathway: Urea-Based Compounds with Nanomolar Potency on Target and Low-Micromolar Whole-Cell Activity.

The methyl-d-erythritol phosphate (MEP) pathway has emerged as an interesting target in the fight against antimicrobial resistance. The pathway is essential in many human pathogens, including (), but is absent in human cells. In the present study, we report on the discovery of a new chemical class targeting IspD, the third enzyme in the pathway.