Development of narrow-spectrum topoisomerase-targeting antibacterials against mycobacteria.

New 2-pyrrolamidobenzothiazole-based inhibitors of mycobacterial DNA gyrase were discovered. Among these, compounds 49 and 51, show excellent antibacterial activity against Mycobacterium tuberculosis and Mycobacterium abscessus with a notable preference for mycobacteria. Both compounds can penetrate infected macrophages and reduce intracellular M. tuberculosis load. Compound 51 is a potent inhibitor of DNA gyrase (M. tuberculosis DNA gyrase IC50 = 4.1 nM, Escherichia coli DNA gyrase IC50 of <10 nM), selective for bacterial topoisomerases. It displays low MIC90 values (M. tuberculosis: 0.63 µM; M. abscessus: 2.5 µM), showing specificity for mycobacteria, and no apparent toxicity. Compound 49 not only displays potent antimycobacterial activity (MIC90 values of 2.5 µM for M. tuberculosis and 0.63 µM for M. abscessus) and selectivity for mycobacteria but also exhibits favorable solubility (kinetic solubility = 55 µM) and plasma protein binding (with a fraction unbound of 2.9 % for human and 4.7 % for mouse). These findings underscore the potential of fine-tuning molecular properties to develop DNA gyrase B inhibitors that specifically target the mycobacterial chemical space, mitigating the risk of resistance development in non-target pathogens and minimizing harm to the microbiome.

Can Early Post-Operative Scoring of Non-Traumatic Amputees Decrease Rates of Revision Surgery?

Background and Objectives: Medical registries evolved from a basic epidemiological data set to further applications allowing deriving decision making. Revision rates after non-traumatic amputation are high and dramatically impact the following rehabilitation of the amputee. Risk scores for revision surgery after non-traumatic lower limb amputation are still missing. The main objective was to create an amputation registry allowing us to determine risk factors for revision surgery after non-traumatic lower-limb amputation and to develop a score for an early detection and decision-making tool for the therapeutic course of patients at risk for non-traumatic lower limb amputation and/or revision surgery. Materials and Methods: Retrospective data analysis was of patients with major amputations lower limbs in a four-year interval at a University Hospital of maximum care. Medical records of 164 patients analysed demographics, comorbidities, and amputation-related factors. Descriptive statistics analysed demographics, prevalence of amputation level and comorbidities of non-traumatic lower limb amputees with and without revision surgery. Correlation analysis identified parameters determining revision surgery. Results: In 4 years, 199 major amputations were performed; 88% were amputated for non-traumatic reasons. A total of 27% of the non-traumatic cohort needed revision surgery. Peripheral vascular disease (PVD) (72%), atherosclerosis (69%), diabetes (42%), arterial hypertension (38%), overweight (BMI > 25), initial gangrene (47%), sepsis (19%), age > 68.2 years and nicotine abuse (17%) were set as relevant within this study and given a non-traumatic amputation score. Correlation analysis revealed delayed wound healing (confidence interval: 64.1% (47.18%; 78.8%)), a hospital length of stay before amputation of longer than 32 days (confidence interval: 32.3 (23.2; 41.3)), and a BKA amputation level (confidence interval: 74.4% (58%; 87%)) as risk factors for revision surgery after non-traumatic amputation. A combined score including all parameters was drafted to identify non-traumatic amputees at risk for revision surgery. Conclusions: Our results describe novel scoring systems for risk assessment for non-traumatic amputations and for revision surgery at non-traumatic amputations. It may be used after further prospective evaluation as an early-warning system for amputated limbs at risk of revision.