Pathway to Independence Awards (K99/R00): Funding Dynamics and Prediction of Future National Institutes of Health Research Project Funding.

Purpose: The authors used the National Institutes of Health (NIH) RePORTER (Research Portfolio Online Reporting Tools) to evaluate funding trends and historic NIH investment increase in the K99 award pathway and examine whether R00 to R01 or R21 achievement time correlated with the future success of an early-stage NIH-funded investigator.

Method: All K99 awards and funding data in this study were limited to all clinical departments. The authors identified all researchers and awards through a K99 search from fiscal years (FYs) 2007 to 2022 across all clinical departments and investigated trends in K99 awards and funding from NIH FYs 2007 to 2022.

National Institutes of Health Funding Gaps for Principal Investigators.

Importance: Early-stage and established investigators compete for a limited supply of funds from the National Institutes of Health (NIH). Regardless of their previous funding success, many principal investigators (PIs) encounter a funding gap in which they no longer receive ongoing funding from the NIH.

Objective: To determine incidence rates of PI-level funding gaps, the mean funding gap length, and whether these 2 metrics are associated with previous funding success.

Structure-activity relationship of new anti-tuberculosis agents derived from oxazoline and oxazole benzyl esters.

During the syntheses and studies of natural iron chelators (mycobactins), we serendipitously discovered that a simple, small molecule, oxazoline-containing intermediate 3 displayed surprising anti-tuberculosis activity (MIC of 7.7 microM, average). Herein we report elaboration of SAR around this hit as well as the syntheses and evaluation of a hundred oxazoline- and oxazole-containing compounds derived from an efficient three step process: 1) formation of beta-hydroxy amides with serine or threonine; 2) cyclization to afford oxazolines; and 3) dehydration to give the corresponding oxazoles.

Co-opting the cell wall in fighting methicillin-resistant Staphylococcus aureus: potent inhibition of PBP 2a by two anti-MRSA beta-lactam antibiotics.

Methicillin-resistant Staphylococcus aureus (MRSA) is a global bacterial scourge that has become resistant to many classes of antibiotics, and treatment options for MRSA infections are limited. The cause of MRSA resistance to all commercially available beta-lactam antibiotics is the acquisition of the gene mecA, which encodes penicillin-binding protein 2a (PBP 2a). PBP 2a is a transpeptidase, which in contrast to the other transpeptidases of S.

Metabolism of (4-phenoxyphenylsulfonyl) methylthiirane, a selective gelatinase inhibitor.

(4-Phenoxyphenylsulfonyl)methylthiirane (compound 1) is a highly selective and potent inhibitor of gelatinases that shows considerable promise in animal models for cancer and stroke. The metabolism of compound 1 was investigated in mice, following intraperitoneal administration at 100 mg/kg. Eight metabolites were identified in plasma and urine.

Metabolism of a highly selective gelatinase inhibitor generates active metabolite.

(4-Phenoxyphenylsulfonyl)methylthiirane (inhibitor 1) is a highly selective inhibitor of gelatinases (matrix metalloproteinases 2 and 9), which is showing considerable promise in animal models for cancer and stroke. Despite demonstrated potent, selective, and effective inhibition of gelatinases both in vitro and in vivo, the compound is rapidly metabolized, implying that the likely activity in vivo is due to a metabolite rather than the compound itself. To this end, metabolism of inhibitor 1 was investigated in in vitro systems.

Mechanistic characterization of the bifunctional aminoglycoside-modifying enzyme AAC(3)-Ib/AAC(6')-Ib' from Pseudomonas aeruginosa.

A recently discovered bifunctional antibiotic-resistance enzyme named AAC(3)-Ib/AAC(6')-Ib', from Pseudomonas aeruginosa, catalyzes acetylation of aminoglycoside antibiotics. Since both domains are acetyltransferases, each was cloned and purified for mechanistic studies. The AAC(3)-Ib domain appears to be highly specific to fortimicin A and gentamicin as substrates, while the AAC(6')-Ib' domain exhibits a broad substrate spectrum.

Structural basis for antioxidant activity of trans-resveratrol: ab initio calculations and crystal and molecular structure.

From the experimental crystal structure and ab initio calculations on resveratrol and its derivatives, structural features of mechanistic importance are described. The molecular structure reveals the relative coplanarity of the trans-stilbene skeleton, and the molecular packing in the solid state shows an extensive hydrogen bond network that elucidates the flip-flop motion of the three hydroxyl groups that alternately form and break H bonds with each of the neighboring phenolic oxygens. The dynamic behavior provoked by the alternation of hydrogen bond formation and breaking can result in the ready mobility of up to three hydrogen atoms per resveratrol molecule that can be transferred to reactive oxidants that are rich in electron density.