Hyaluronidase impacts exposures of long-acting injectable paliperidone palmitate in rodent models.

A significant challenge in the development of long-acting injectable drug formulations, especially for anti-infective agents, is delivering an efficacious dose within a tolerable injection volume. Co-administration of the extracellular matrix-degrading enzyme hyaluronidase can increase maximum tolerable injection volumes but is untested for this benefit with long-acting injectable formulations. One concern is that hyaluronidase could potentially alter the tissue response surrounding an injection depot, a response known to be important for drug release kinetics of long-acting injectable formulations. The objective of this pilot study was to evaluate the impact of co-administration of hyaluronidase on the drug release kinetics, pharmacokinetic profiles, and injection site histopathology of the long-acting injectable paliperidone palmitate for up to four weeks following intramuscular injection in mouse and rat models. In both species, co-administration of hyaluronidase increased paliperidone plasma exposures the first week after injection but did not negate the overall long-acting release nature of the formulation. Hyaluronidase-associated modification of the injection site depot was observed in mice but not in rats. These findings suggest that further investigation of hyaluronidase with long-acting injectable agents is warranted.

Protective effect of Achyranthes aspera against compound 48/80, histamine and ovalbumin-induced allergic disorders in murine model.

BACKGROUND: Achyranthes aspera L. (family Amaranthaceae) is a plant species valued in Ayurveda for the treatment of respiratory ailments. Scientific validation of its antiallergic potential was aimed. METHODS AND RESULTS: Three extracts of A. aspera [aqueous (AaAq), hydroalcoholic (AaHA), ethanolic (AaEt)] were evaluated for their potency against C48/80-induced anaphylaxis in mice at 200 mg/kg BW oral dose. The effective dose of the most potent extract was determined through its effect on C48/80-induced anaphylaxis, and was further analyzed through its effect on mast cell degranulation, histamine-induced bronchospasm and ovalbumin (OVA)-induced asthma in a murine model. Among the three extracts, AaAq was found to be most potent at 200 mg/kg BW. AaAq 400 (400 mg/kg BW) was found to be the most effective dose in terms of inhibition of mortality and histamine level. AaAq 400 prevented the peritoneal and mesenteric mast cells from undergoing morphological changes due to degranulation induced by C48/80. Further, AaAq 400 delayed pre-convulsive time in histamine-induced bronchospasm. In the OVA-induced asthma model, AaAq 400 inhibited the level of inflammatory cell count in blood, bronchoalveolar lavage fluid and peritoneal fluid of mice. The Th2 cytokines (IL-4, IL-5, IL-13), TGF-ß and OVA-specific IgE were also reduced as evaluated by ELISA. Also, significant reduction in IL-5 (an eosinophilia indicator) transcript abundance and lung inflammatory score was observed. AaAq was safe up to 4000 mg/kg BW. CONCLUSIONS: Thus AaAq 400 possesses significant antiallergic potential and acts via attenuation of C48/80-induced anaphylaxis and inhibition of mast cell degranulation. It reduces pre-convulsive dyspnea in histamine-induced bronchospasm and Th2 cytokines in asthmatic mice.

The second wave of COVID-19 wreaked havoc: A look at clinical and laboratory parameters of survivors and non-survivors admitted to Intensive Care Unit, a single-centered retrospective study.

Background: The second wave of COVID-19 was disastrous and claimed many lives in India and abroad. The most challenging task was to provide the required treatment as per the patient's condition, within a limited span of time. The lack of prognostic predictors at the time of admission led to failure in prioritizing the patient's need for intensive care. Aim: This study was conducted to find out the clinical and laboratory parameters at the time of admission to ICU as predictors of outcomes in COVID-19 patients, which can help in judicious utilization of the available resources for better patient care. Subjects and Methods: Study comprises of 161 ICU admitted patients. Study of clinical traits, comorbidities, test results, and demographic variables were carried out among survivors and non-survivor. Result: Maximum death were patients of age group 21-30 years and male gender. Mortality in hypertensives, diabetics, and patients with sepsis were found to be statistically significant. Patients who developed ARDS and pneumonia or needed ventilation died invariably. High levels of laboratory parameters like IL-6, LDH, PT, INR, aPTT, ferritin, WBC count, and D-dimer were significantly associated with poor outcomes and at a particular cutoff had optimum sensitivity and specificity to predict mortality in ICU admitted COVID-19 patients. At the same time, low lymphocyte count and PaO2/FiO2 ratio was significantly associated with bad prognosis (P < 0.05). Conclusion: This paper will help in prioritizing patients in ICU who need special attention especially at the time of meager supply of resources.

Enhanced Anti-Proliferative Effect of Carboplatin in Ovarian Cancer Cells Exploiting Chitosan-Poly (Lactic Glycolic Acid) Nanoparticles.

OBJECTIVE: The present article aimed to enhance the therapeutic efficacy of carboplatin (CP) using the formulation of chitosan-poly (lactic glycolic acid) nanoparticles (CS-PLGA NPs). METHODS: Nanoparticles were synthesized by an ionic gelation method and were characterized for their morphology, particle size, and surface potential measurements by TEM and zeta sizer. This study was highlighted for the evaluation of drug entrapment, loading and in vitro drug release capabilities of the prepared nanoparticles by spectrophotometric analysis. The stability study was also conducted after 3 months for their particle size, zeta potential, drug loading and encapsulation efficiencies. Further, ovarian cancer cell line PEO1 was used to evaluate the toxicity and efficacy of nano-formulation by MTT assay. Additionally, the study was evaluated for apoptosis using flow cytometric analysis. RESULTS: The CS-PLGA-CP NPs were uniform and spherical in shape. The particle size and zeta potential of CS-PLGA-CP NPs were measured to be 156 ±6.8 nm and +52 ±2.4 mV, respectively. High encapsulation (87.4 ± 4.5%) and controlled retention capacities confirmed the efficiency of the prepared nanoparticles in a time and dose-dependent manner. The cytotoxicity assay results also showed that CS-PLGA-CP NPs have a high efficiency on PEO1 cells compared to the free drug. The flow cytometric result showed 64.25% of the PEO1 cells were apoptotic, and 8.42% were necrotic when treated with CS-PLGA-CP NPs. CONCLUSION: Chitosan-PLGA combinational polymeric nanoparticles were not only steady but also non-toxic. Our experiments revealed that the chitosan-PLGA nanoparticles could be used as a challenging vehicle candidate for drug delivery for the therapeutic treatment of ovarian cancer.

The Novel Oxazolidinone TBI-223 Is Effective in Three Preclinical Mouse Models of Methicillin-Resistant Staphylococcus aureus Infection.

Staphylococcus aureus is an important cause of various infections in humans, including bacteremia, skin and soft tissue infections, and infections associated with implanted medical devices. The emergence of hospital- and community-acquired methicillin-resistant Staphylococcus aureus (MRSA) underscores the urgent and unmet need to develop novel, safe, and effective antibiotics against these multidrug-resistant clinical isolates. Oxazolidinone antibiotics such as linezolid have excellent oral bioavailability and provide coverage against MRSA infections. However, their widespread and long-term use is often limited by adverse effects, especially myelosuppression. TBI-223 is a novel oxazolidinone with potentially reduced myelosuppression, compared to linezolid, but its efficacy against MRSA infections is unknown. Therefore, the preclinical efficacy of TBI-223 (80 and 160 mg/kg twice daily) was compared with that of linezolid (40 and 80 mg/kg twice daily) and sham treatment in mouse models of MRSA bacteremia, skin wound infection, and orthopedic-implant-associated infection. The dosage was selected based on mouse pharmacokinetic analysis of both linezolid and TBI-223, as well as measurement of the MICs. In all three models, TBI-223 and linezolid had comparable dose-dependent efficacies in reducing bacterial burden and disease severity, compared with sham-treated control mice. Taken together, these findings indicate that TBI-223 represents a novel oxazolidinone antibiotic that may provide an additional option against MRSA infections. Future studies in larger animal models and clinical trials are warranted to translate these findings to humans. IMPORTANCE Staphylococcus aureus is the predominant cause of bloodstream, skin, and bone infections in humans. Resistance to commonly used antibiotics is a growing concern, making it more difficult to treat staphylococcal infections. Use of the oxazolidinone antibiotic linezolid against resistant strains is hindered by high rates of adverse reactions during prolonged therapy. Here, a new oxazolidinone named TBI-223 was tested against S. aureus in three mouse models of infection, i.e., bloodstream infection, skin infection, and bone infection. We found that TBI-223 was as effective as linezolid in these three models. Previous data suggest that TBI-223 has a better safety profile than linezolid. Taken together, these findings indicate that this new agent may provide an additional option against MRSA infections. Future studies in larger animal models and clinical trials are warranted to translate these findings to humans.

Structure-Activity Relationship of Penem Antibiotic Side Chains Used against Mycobacteria Reveals Highly Active Compounds.

The rise of antibiotic-resistant Mycobacterium tuberculosis and non-tuberculous mycobacterial infections has placed ever-increasing importance on discovering new antibiotics to treat these diseases. Recently, a new penem, T405, was discovered to have strong antimicrobial activity against M. tuberculosis and Mycobacteroides abscessus. Here, a penem library of C2 side-chain variants was synthesized, and their antimicrobial activities were evaluated against M. tuberculosis H37Rv and M. abscessus ATCC 19977. Several new penems with antimicrobial activity stronger than the standard-of-care carbapenem antibiotics were identified with some candidates improving on the activity of the lead compound, T405. Moreover, many candidates showed little or no increase in the minimum inhibitory concentration in the presence of serum compared to the highly protein-bound T405. The penems with the strongest activity identified in this study were then biochemically characterized by reaction with the representative l,d-transpeptidase LdtMt2 and the representative penicillin-binding protein d,d-carboxypeptidase DacB2.

2D-DIGE based urinary proteomics and functional enrichment studies to reveal novel Mycobacterium tuberculosis and human protein biomarker candidates for pulmonary tuberculosis.

In the absence of a sensitive and specific diagnostic modality capable of detecting all forms of tuberculosis (TB), proteomics may identify specific Mycobacterium tuberculosis (M.tb) proteins in urine, with a potential as biomarkers. To identify candidate biomarkers for TB, proteome profile of urine from pulmonary TB patients was compared with non-disease controls (NDC) and disease controls (DC, Streptococcus pneumonia infected patients) using a combination of two-dimensional difference gel electrophoresis (2D-DIGE) and liquid chromatography tandem mass spectrometry (LCMS/MS). Eleven differentially expressed host proteins and Eighteen high abundant M.tb proteins were identified. Protein-protein interactome (PPI) and functional enrichment analyses like Gene Ontologies, Reactome pathway etc. demonstrated that the human proteins mainly belong to extracellular space and show physiological pathways for immune response and hematological disorders. Whereas, M.tb proteins belong to the cell periphery, plasma membrane and cell wall, and demonstrated catalytic, nucleotide binding and ATPase activities along with other functional processes. The study findings provide valuable inputs about the biomarkers of TB and shed light on the probable disease consequences as an outcome of the bacterial pathogenicity.

Assessment of knowledge and their practices regarding malaria among members of Village Health Sanitation Committee in rural Uttar Pradesh: A cross-sectional study.

Background: In 2019, the global number of malaria cases was estimated at 229 million. An estimated 409,000 deaths were attributed to malaria in 2019. Under-five children are the most susceptible to malaria, accounting for 67% (274,000) of all malaria deaths worldwide in 2019. This study aimed to assess knowledge and practices regarding malaria among Village Health Sanitation Committee (VHSC) members in rural Uttar Pradesh. Methodology: This cross-sectional study was conducted in the villages of four districts of Uttar Pradesh with high malaria burden. In the present study, 484 participants were interviewed from four districts of Uttar Pradesh. Results: Nearly all the participants (97.1%) have heard about malaria. Majority of the participants (97.1) were aware that mosquito bites spread malaria. However, many participants were also having a false awareness that malaria is spread by other modes like drinking contaminated water, touching each other, eating contaminated food, and so on. More than half of the participants told that mosquitoes are responsible for malaria breeds in stagnant clean water (25.6%) and stagnant dirty water (28.5%). Nearly half of them were aware that mosquitoes' biting time was sunset (42.1%) and sunrise (7.8%). Conclusion: In the present study, many participants were having a false awareness that malaria is spread by other modes like drinking contaminated water, touching each other, eating contaminated food, and so on. Even the knowledge regarding any government program for the prevention and control of malaria of the mosquitoes was very weak. There is an urgent requirement of increasing knowledge among the VHSC members to reduce the malaria burden in the country.

Efficacy of Long-Acting Bedaquiline Regimens in a Mouse Model of Tuberculosis Preventive Therapy.

Rationale: Completion of preventive therapy is a major bottleneck in global tuberculosis control. Long-acting injectable drug formulations would shorten therapy administration and may thereby improve completion rates. Recently, a long-acting formulation of bedaquiline demonstrated antituberculosis activity for up to 12 weeks after injection in a validated mouse model of preventive therapy. Objectives: The objectives of this study were to 1) determine the total duration of activity after an injection of long-acting bedaquiline and 2) evaluate the activity of regimens comprised of long-acting bedaquiline plus short (2-4 wk) oral companion courses of bedaquiline, with or without rifapentine, using the validated mouse model of tuberculosis preventive therapy. Methods: After the establishment of a stable Mycobacterium tuberculosis lung infection in bacillus Calmette-Guérin (BCG)-immunized BALB/c mice, treatment was initiated with 1 of 12 randomly assigned regimens. In addition to positive and negative controls, six regimens included one or two injections of long-acting bedaquiline (alone or with oral bedaquiline with or without rifapentine), and four comparator regimens consisted of oral agents only. Lung bacterial burden was measured monthly for up to 28 weeks. Measurements and Main Results: One injection of long-acting bedaquiline at 160 mg/kg exerted antituberculosis activity for 12 weeks. Compared with the positive control (daily isoniazid-rifapentine for 4 wk), six regimens had equivalent bactericidal activity (including two all-oral comparator regimens), and two regimens had superior sterilizing activity: one injection with 2 weeks of oral bedaquiline and high-dose rifapentine; and two injections with 4 weeks of oral bedaquiline. Conclusions: Long-acting injectable bedaquiline has significant potential for shortening tuberculosis preventive therapy.

Relation Between HbA1c and Lipid Profile Among Prediabetics, Diabetics, and Non-diabetics: A Hospital-Based Cross-Sectional Analysis.

INTRODUCTION: An unusually high blood glucose level is a hallmark of diabetes mellitus, with an imbalance between insulin levels and insulin sensitivity leading to an insulin functional deficit. Since it serves as both a risk indicator and a gauge of long-term glycemic control, the HbA1c concentration is a crucial component of standard diabetes treatment. The use of the HbA1c concentration in the diagnosis of diabetes is expanding as the test's accuracy increases. Dyslipidemic profiles can appear before type 2 diabetes manifests itself and are independent risk factors for the disease. Additionally, dyslipidemia, especially in diabetics, might affect pancreatic beta-cell survival and activity. This study was undertaken with the aim to find out any correlation between HbA1c and lipid profile among diabetics, prediabetics, and non-diabetics. METHODS: A total of 1,000 individuals with age 18-60 years were included in the study (non-diabetics = 186, prediabetics = 238, diabetics = 576). HbA1c was estimated by capillary electrophoresis and a lipid profile was done using a fully automatic chemistry analyzer. RESULT: Diabetes was found to be significantly associated with dyslipidemia. In diabetics, a statistically significant increase in the level of triglyceride and very low-density lipoprotein (VLDL) was seen as compared to prediabetics. Diabetic women were found to be significantly more dyslipidemic as compared to diabetic males. The mean HbA1c among diabetics was found to be 8.3. CONCLUSION: In hyperglycemia-induced dyslipidemia, raised triglyceride and VLDL were the most common findings, and combined lipid abnormalities were more commonly seen as compared to a single abnormality in the lipid profile. Patients with poor glycemic control more commonly develop dyslipidemia, which may be a reason for an increased incidence of cardiovascular catastrophes in such patients.

Teacher professional development for disability inclusion in low- and middle-income Asia-Pacific countries: An evidence and gap map.

Background: In the Asia-Pacific region, around one-third of the children who are out-of-school have a disability and given that teacher readiness and capability are key contributors for inclusive education, it is high time for a mapping of disability inclusive teacher professional development (TPD) interventions in this region. Objectives: The key objective of this evidence and gap map (EGM) is to locate evidence on interventions for in-service TPD focussing on education for the inclusion of students with a disability in low- and middle-income countries (LMICs) in the Asia-Pacific region. Search Methods: A broad range of bibliographic databases and repositories were searched electronically to identify the evidence published between January 2000 and December 2021. Key search platforms included the British Education Index (BEI), Education Research Complete (ERC), Education Resources Information Center (ERIC), SCOPUS, 3ie Development Evidence Portal (Evidence Hub) and the Campbell Collaborations Systematic Reviews and EGMs portal (Better evidence for a better world). In addition, potential program evaluations/impact reports, reviews, case studies, and program descriptions/summaries were sought through 'snowballing' based on searching bibliographies and reference lists of papers located during the search process, as well as specific searches of relevant grey literature. Selection Criteria: To be eligible for inclusion, studies had to contain sufficient details about TPD interventions that support early childhood educators and kindergarten to Year 12 teachers to understand the needs of students with disabilities and aid them to create inclusive mainstream classrooms and/or provide improved support for students with disabilities in special education settings. Data Collection and Analysis: A total of 820 records were entered into the MS Excel file in which the entire data extraction process was managed. All records were screened against the predefined inclusion and exclusion criteria. Data were extracted independently by two reviewers and any differences were resolved through consultations. All included studies and their characteristics were extracted from the MS Excel file and uploaded to the ACER server in.csv file format. The interactive, online EGM is available here: https://datavis.acer.org/gem/disability-inclusion-TPD/. Main Results: Fifty studies from 16 countries out of the 41 LMICs in the Asia-Pacific region were identified, whereby Thailand had the largest number of studies with evidence (7) followed by China, Vietnam, and India (5 each). Two main gaps in research about professional learning were identified. First, only three studies reported interventions aimed at supporting mental health among students with a disability. Second, no studies were found that reported on how teachers could support positive student behaviour. These gaps are important because research has persistently suggested that experiencing disability is an important risk factor for young people developing mental health conditions. Authors' Conclusions: This report illustrates the critical value of evaluating and publishing evidence from disability inclusive TPD interventions in LMICs, including any that are ongoing, or are components of highly resource intensive large-scale education sector programs.

Agricultural pesticide use and misuse: A study to assess the cognizance and practices among North Indian farmers.

Introduction: Farmers' cognizance regarding pesticide use and overuse is limited and their practices for handling of pesticides is unsatisfactory. However, their perception concerning risks and safety of pesticides play a very important role in safe spraying and indirectly protect them from adverse health hazards. Objective: To assess the cognizance about use and risks of overuse of pesticides and evaluate practices for the storage, preparation, and disposal of pesticides. Material and Methods: A cross-sectional study was conducted among 387 farmers of Lucknow who fulfilled the inclusion criteria. A multistage random sampling was done to interview the farmers. A pretested structured questionnaire was to collect the information regarding the cognizance about use and risks of overuse of pesticides and evaluate practices for the storage, preparation, and disposal of pesticides. Results: More than half (55%) of the farmers did not read and follow the pesticide label. Maximum (80.2%) were unaware that pesticides are banned or restricted for use. Thirty-seven percent did not know that some pesticides may cause lethal intoxications. Majority of the farmers (42.6%) stored the pesticides anywhere in the house. More than two-thirds of the farmers (69.7%) mixed only needed pesticides followed by a low percentage of them applying on other crops (15.8%) and dispose in the field (11.7%). Conclusion: The study concludes that cognizance and practices of the farmers for pesticide use and risks associated with it was not satisfactory and exposes them to adverse health outcomes.

In Vitro Activity of Bedaquiline and Imipenem against Actively Growing, Nutrient-Starved, and Intracellular Mycobacterium abscessus.

Mycobacterium abscessus lung disease is difficult to treat due to intrinsic drug resistance and the persistence of drug-tolerant bacteria. Currently, the standard of care is a multidrug regimen with at least 3 active drugs, preferably including a ß-lactam (imipenem or cefoxitin). These regimens are lengthy and toxic and have limited efficacy. The search for more efficacious regimens led us to evaluate bedaquiline, a diarylquinoline licensed for treatment of multidrug-resistant tuberculosis. We performed in vitro time-kill experiments to evaluate the activity of bedaquiline alone and in combination with the first-line drug imipenem against M. abscessus under various conditions. Against actively growing bacteria, bedaquiline was largely bacteriostatic and antagonized the bactericidal activity of imipenem. Contrarily, against nutrient-starved persisters, bedaquiline was bactericidal, while imipenem was not, and bedaquiline drove the activity of the combination. In an intracellular infection model, bedaquiline and imipenem had additive bactericidal effects. Correlations between ATP levels and the bactericidal activity of imipenem and its antagonism by bedaquiline were observed. Interestingly, the presence of Tween 80 in the media affected the activity of both drugs, enhancing the activity of imipenem and reducing that of bedaquiline. Overall, these results show that bedaquiline and imipenem interact differently depending on culture conditions. Previously reported antagonistic effects of bedaquiline on imipenem were limited to conditions with actively multiplying bacteria and/or the presence of Tween 80, whereas the combination was additive or indifferent against nutrient-starved and intracellular M. abscessus, where promising bactericidal activity of the combination suggests it may have a role in future treatment regimens.

Assessment of carbapenems in a mouse model of Mycobacterium tuberculosis infection.

We present further study of a subset of carbapenems, arising from a previously reported machine learning approach, with regard to their mouse pharmacokinetic profiling and subsequent study in a mouse model of sub-acute Mycobacterium tuberculosis infection. Pharmacokinetic metrics for such small molecules were compared to those for meropenem and biapenem, resulting in the selection of two carbapenems to be assessed for their ability to reduce M. tuberculosis bacterial loads in the lungs of infected mice. The original syntheses of these two carbapenems were optimized to provide multigram quantities of each compound. One of the two experimental carbapenems, JSF-2204, exhibited efficacy equivalent to that of meropenem, while both were inferior to rifampin. The lessons learned in this study point toward the need to further enhance the pharmacokinetic profiles of experimental carbapenems to positively impact in vivo efficacy performance.

PROTOCOL: Teacher professional development for disability inclusion in low- and middle-income Asia-Pacific countries: An evidence and gap map.

According to prior research, teacher readiness and capability are key contributors for successful transition towards disability inclusive education, yet in-service teacher professional development for disability inclusion remains an under-researched area. The key objective of this evidence and gap map (EGM) is to locate evidence on interventions for disability inclusion focused teacher professional development (TPD) in low-to-middle-income-countries (LMICs) in the Asia-Pacific region. As such, it will illustrate different levels of evidence for TPD interventions as well as where there is no evidence (i.e., gaps). In other words, the EGM can make agencies aware where they might be operating in an area that is evidence-free or evidence-weak so they can take up interventions that are evidence-based or collect evidence for the intervention they are presently supporting. Thus, the ultimate goal for the EGM is to assist funders and implementing agencies when making decisions as to how to support LMICs in the region to reach their aim of developing quality teachers for the global inclusive education agenda (target SDG 4.c).

Development of a penem antibiotic against Mycobacteroides abscessus.

ß-lactams are the most widely used antibiotic class to treat bacterial infections in humans. Mycobacteroides abscessus is an emerging pulmonary pathogen resistant to most antibiotics, including penicillins and cephalosporins. With no current FDA-approved treatment and cure rates <50%, there is a pressing need for effective therapies. Here we report T405, a new ß-lactam of the penem subclass that exhibits potent activity against M. abscessus and a panel of drug-resistant strains isolated from cystic fibrosis patients. Additionally, in combination with the ß-lactamase inhibitor avibactam, the rate of spontaneous resistance of M. abscessus to T405 approached the limit of detection. Lastly, we show the favorable pharmacokinetic profile of T405 in mice and the absence of toxicity at elevated dosage, which support the clinical potential of this compound.

N-Trifluoromethylthiolated Sulfonimidamides and Sulfoximines: Anti-microbial, Anti-mycobacterial, and Cytotoxic Activity.

Herein we demonstrate the expanded utility of a recently described N-trifluoromethylthiolation protocol to sulfonimidamide containing substances. The novel N-trifluoromethylthio sulfonimidamide derivatives thus obtained were evaluated for antibacterial activity against Mycobacterium tuberculosis (M. tb.) and Mycobacterium abscessus and Gram + Ve (Streptococcus aureus, Bacillus subtilis), and Gram - Ve (Escherichia coli, Pseudomonas aeruginosa) bacteria. Two compounds, 13 and 15 showed high antimycobacterial activity with MIC value of 4-8 µg/mL; i.e. comparable to WHO recommended first line antibiotic for TB infection ethambutol. The same compounds were also found to be cytotoxic in HepG2 cells (compound 13 IC50 = 15 µg/mL; compound 15 IC50 = 65 µg/mL). A structure activity relationship, using matched pair analysis, gave the unexpected conclusion that the trifluoromethylthio moiety was responsible for the cellular and bacterial toxicity. Given the increasing use of the trifluoromethylthio group in contemporary medicinal chemistry, this observation calls for considerations before implementation of the functionality in drug design.

An Ancient Harappan Genome Lacks Ancestry from Steppe Pastoralists or Iranian Farmers.

We report an ancient genome from the Indus Valley Civilization (IVC). The individual we sequenced fits as a mixture of people related to ancient Iranians (the largest component) and Southeast Asian hunter-gatherers, a unique profile that matches ancient DNA from 11 genetic outliers from sites in Iran and Turkmenistan in cultural communication with the IVC. These individuals had little if any Steppe pastoralist-derived ancestry, showing that it was not ubiquitous in northwest South Asia during the IVC as it is today. The Iranian-related ancestry in the IVC derives from a lineage leading to early Iranian farmers, herders, and hunter-gatherers before their ancestors separated, contradicting the hypothesis that the shared ancestry between early Iranians and South Asians reflects a large-scale spread of western Iranian farmers east. Instead, sampled ancient genomes from the Iranian plateau and IVC descend from different groups of hunter-gatherers who began farming without being connected by substantial movement of people.

New ß-Lactamase Inhibitors Nacubactam and Zidebactam Improve the In Vitro Activity of ß-Lactam Antibiotics against Mycobacterium abscessus Complex Clinical Isolates.

The new diazabicyclooctane-based ß-lactamase inhibitors avibactam and relebactam improve the in vitro activity of ß-lactam antibiotics against bacteria of the Mycobacterium abscessus complex (MABC). Here, we evaluated the in vitro activities of two newer diazabicyclooctane-based ß-lactamase inhibitors in clinical development, nacubactam and zidebactam, with ß-lactams against clinical isolates of MABC. Both inhibitors lowered the MICs of their partner ß-lactams, meropenem (8-fold) and cefepime (2-fold), respectively, and those of other ß-lactams, similar to prior results with avibactam and relebactam.

In Vitro Activity of New Tetracycline Analogs Omadacycline and Eravacycline against Drug-Resistant Clinical Isolates of Mycobacterium abscessus.

Tigecycline is used in multidrug regimens for salvage therapy of Mycobacterium abscessus infections but is often poorly tolerated and has no oral formulation. Here, we report similar in vitro activity of two newly approved tetracycline analogs, omadacycline and eravacycline, against 28 drug-resistant clinical isolates of M. abscessus complex. Since omadacycline and eravacycline appear to be better tolerated than tigecycline and since omadacycline is also formulated for oral dosing, these tetracycline analogs may represent new treatment options for M. abscessus infections.