Mycobacterium tuberculosis is the cause of the world’s most deadly infectious disease. Efforts are underway to target the methionine biosynthesis pathway, as it is not part of the host metabolism. The homoserine transacetylase MetX converts l-homoserine to O-acetyl-l-homoserine at the committed step of this pathway. In order to facilitate structure-based drug design, we determined the high-resolution crystal structures of three MetX proteins, including M. tuberculosis (MtMetX), Mycolicibacterium abscessus (MaMetX), and Mycolicibacterium hassiacum (MhMetX). A comparison of homoserine transacetylases from other bacterial and fungal species reveals a high degree of structural conservation amongst the enzymes. Utilizing homologous structures with bound cofactors, we analyzed the potential ligandability of MetX. The deep active-site tunnel surrounding the catalytic serine yielded many consensus clusters during mapping, suggesting that MtMetX is highly druggable.

Mycobacterium tuberculosis is cause of the world's most deadly infectious disease. Efforts are underway to target the methionine biosynthesis pathway, as it is not part of the host metabolism. The homoserine transacetylase MetA converts L-homoserine to O-acetyl-Lhomoserine at the committed step of this pathway. In order to facilitate structure-based drug design, we determined the high-resolution crystal structures of three MetA proteins, including M. tuberculosis (MtMetA), Mycolicibacterium abscessus (MaMetA), and Mycolicibacterium hassiacum (MhMetA). Comparison to other homoserine transacetylase family-members reveals a high degree of structural conservation. Utilizing homologous structures with bound cofactors, we analyzed the potential ligandability of MetA. The deep active-site tunnel surrounding the catalytic serine yielded a number of consensus clusters during mapping, suggesting thatMtMetA is highly druggable.

BACKGROUND:Improving neurosurgical quality metrics necessitates the analysis of patient safety indicator (PSI) 04, a measure of failure to rescue (FTR).OBJECTIVE:To demonstrate that PSI 04 is not an appropriate measure for capturing FTR within neurosurgery.METHODS:We conducted a single-center retrospective cohort study. Patients from January 1, 2017 to June 1, 2021, who sustained a PSI 04-attributed complication (pneumonia, deep vein thrombosis/pulmonary embolism, sepsis, shock/cardiac arrest, or gastrointestinal hemorrhage/acute ulcer), underwent a neurosurgical procedure, had inpatient mortality, and were identified using patient safety indicator 04 (PSI 04) tracking algorithm. The primary outcome was whether the attributed PSI 04 designation was the primary driver of mortality.RESULTS:We identified 67 patients who met the PSI 04 criteria (median age, 61 years; female sex, 43.4%). Nearly 20% of patients met the PSI complication criteria before admission. Patients who underwent emergent bedside procedures were more likely to present with a poor Glasgow Coma Scale (P = .016), more likely to be intubated before admission (P = .016), and less likely to have mortality due to a PSI 04-related complication (P = .002). PSI 04-related complications were identified as the cause of death in only 43.2% of cases. Procedures occurring in the interventional radiology suite (odds ratio, 23.2; 95% CI, 3.5-229.3; P = .003) or the operating room (odds ratio, 6.2; 95% CI, 1.25-39.5; P = .03) were more likely to have mortality because of a PSI 04-related complication compared with bedside procedures.CONCLUSION:In total, 65.7% of patients were inappropriately flagged as meeting PSI 04 criteria. PSI 04 currently identifies patients with complications unrelated to operating room procedures. Improvement in patient safety within neurosurgery necessitates the development of a subspecialty specific measure to capture FTR.