Solithromycin in Combination with Other Antimicrobial Agents Against the Carbapenem Resistant Klebsiella pneumoniae (CRKP).

Klebsiella pneumoniae is considered as the most common pathogen of hospital-acquired pneumonia. K. pneumoniae has emerged as the superbug which had shown multidrug resistance (MDR) as well as extensively drug resistance. Carbapenem resistant K. pneumoniae (CRKP) has become a menace for the treatment with monotherapy of the patients mainly admitted in intensive care units. Hence, in the present study we collected total 187 sputum isolates of K. pneumoniae and performed the antimicrobial susceptibility testing by using the automated Vitek-2 system and broth micro-dilution method (67 CRKP). The combination study of solithromycin with meropenem, colistin, cefotaxime, piperacillin and tazobactam, nitrofurantoin, tetracycline, levofloxacin, curcumin and nalidixic acid was performed by using checkerboard assay. We observed the high rate of resistance towards ampicillin, cefotaxime, ceftriaxone, cefuroxime and aztreonam. The colistin and tigecycline were the most sensitive drugs. The CRKP were 36%, maximum were from the patients of ICUs. The best synergistic effect of solithromycin was with meropenem and cefotaxime (100%), colistin and tetracycline (80%). So, these combinations can be a choice of treatment for the infections caused by MDR CRKP and other Gram-negative bacteria where the monotherapy could not work.

Burden of Portal Hypertension Complications Is Greater in Liver Transplant Wait-Listed Registrants with End-Stage Liver Disease and Type 2 Diabetes.

BACKGROUND AND AIMS: Impact of type 2 diabetes mellitus (T2DM) in patients with end-stage liver disease (ESLD) awaiting liver transplantation (LT) remains poorly defined. The objective of the present study is to evaluate the relationship between T2DM and clinical outcomes among patients with LT waitlist registrants. We hypothesize that the presence of T2DM will be associated with worse clinical outcomes. METHODS: 593 patients adult (age 18 years or older) who were registered for LT between 1/2010 and 1/2017 were included in this retrospective analysis. The impact of T2DM on liver-associated clinical events (LACE), survival, hospitalizations, need for renal replacement therapy, and likelihood of receiving LT were evaluated over a 12-month period. LACE was defined as variceal hemorrhage, hepatic encephalopathy, and ascites. Kaplan-Meier and Cox regression analysis were used to determine the association between T2DM and clinical outcomes. RESULTS: The baseline prevalence of T2DM was 32% (n = 191) and patients with T2DM were more likely to have esophageal varices (61% vs. 47%, p = 0.002) and history of variceal hemorrhage (23% vs. 16%, p = 0.03). The presence of T2DM was associated with increased risk of incident ascites (HR 1.91, 95% CI 1.11, 3.28, p = 0.019). Patients with T2DM were more likely to require hospitalizations (56% vs. 49%, p = 0.06), hospitalized with portal hypertension-related complications (22% vs. 14%; p = 0.026), and require renal replacement therapy during their hospitalization. Patients with T2DM were less likely to receive a LT (37% vs. 45%; p = 0.03). Regarding MELD labs, patients with T2DM had significantly lower bilirubin at each follow-up; however, no differences in INR and creatinine were noted. CONCLUSION: Patients with T2DM are at increased risk of clinical outcomes. This risk is not captured in MELD score, which may potentially negatively affect their likelihood of receiving LT.

Prediction of Different Risk Factors in Relation to Hyperlipidemia Using Framingham Risk Score and Cholesterol Risk Score in a Tertiary Care Hospital.

BACKGROUND: A condition that affects the circulatory system of the human body is referred to as a cardiovascular disease (CVD). Cardiovascular diseases (CVDs) are responsible for a significant number of fatalities globally. Annually, CVDs result in the demise of 17.9 million people, which accounts for 31% of all fatalities on a global scale. OBJECTIVE: The objective of the study was to assess the demographic profile of diabetic and nondiabetic patients suffering from cardiovascular disease. The aim of the study is to predict risk factors in relation to hyperlipidaemia using two different scales, the Framingham Risk Scale (FRS) and the Cholesterol Risk Calculator (CRC), and to determine the frequency of hypercholesterolemia in relation to CVD. METHODS: A cross-sectional study was conducted in Guru Gobind Singh Medical College and Hospital, Punjab, India. RESULTS: The mean age of patients was found to be M= (51.23), SD= (9.348) years, and among 331 patients (52.6%) were female patients. The mean of Framingham Risk Score was found to be (29.07%). The Framingham Risk Score was found significant with gender and calorie intake below the recommended dietary allowances of the patient (p=0.001). The Framingham Risk Score was found significant with physical activity and employment status of the patients (p= 0.001). In linear regression, the Framingham Risk Score was found significant with the lipid profile of the patients (p=0.001) i.e., the higher the value of cholesterol level, the higher the Framingham Risk Score. The chi-square test showed a significant relation between Cholesterol Risk Score and employment status, physical activity, calorie intake, gender, and occupation of the patients (p=0.001, p=0.001, p=0.001, p=0.004) respectively. CONCLUSION: The present study demonstrated that patients with high Framingham risk score and cholesterol risk score are at increased risk of diabetes and cardiovascular disease. The present study concludes that the FRS is higher in patients below RDA, patients doing low physical activity, and sedentary workers. In order to provide proper assistance and counselling, healthcare professionals must continuously analyze each patient's risk factor for CVD and barriers to healthy and preventive behaviors. There is a lack of comprehensive studies comparing the effectiveness of the Framingham Risk Score and Cholesterol Risk Score in predicting hyperlipidemia and associated cardiovascular risks within the context of a tertiary care hospital setting.

Community perspective and healthcare assessment in malaria endemic states of India: a cross-sectional study protocol.

INTRODUCTION: India's contribution to the malaria burden was highest in South-East Asia Region in 2021, accounting for 79% of the estimated malaria cases and 83% of malaria-related deaths. Intensified Malaria Control Programme supported by Global Funds to Fight against AIDS, Tuberculosis and Malaria has deployed crucial interventions to reduce the overall burden of malaria in India. Evaluation of utilisation of malaria elimination interventions by the community and assessment of the healthcare system is underway in eleven high malaria endemic states in India. Health system preparedness for malaria elimination, logistics, and supply chain management of diagnostic kits and anti-malarial drugs in addition to the knowledge, attitude and practice of the healthcare workers is also being assessed. METHODS AND ANALYSIS: The study is being undertaken in 11 malaria endemic states with a variable annual parasite incidence of malaria. In total, 47 districts (administrative unit of malaria control operations) covering 37 976 households are to be interviewed and assessed. We present here the protocol following which the study is being undertaken at the behest and approval of Ministry of Health and Family Welfare in India. ETHICS AND DISSEMINATION: No patients were involved in the study. Study findings will be shared with Institutional ethics board of National Institute for Malaria Research New Delhi (NIMR) in a timely, comprehensive, accurate, unbiased, unambiguous and transparent manner and to the National Vector-borne Disease (Malaria) Control Programme officers and the Community public who participated. Important findings will be communicated through community outreach meetings which are existing in the Health system. Results will be informed to study participants via local fieldwork supervised by District Malaria Officers. Also findings will be published in reputed journals based on Indian Council of Medical Research (ICMR) publication policy.The ICMR-NIMR ethics committee approved the study via letter No. NIMR/ECM/2023/Feb/14 dated 24 April 2023 for version 5. All standard ethical practices will be followed.

Oncogenes and tumor suppressor genes: functions and roles in cancers.

Cancer, being the most formidable ailment, has had a profound impact on the human health. The disease is primarily associated with genetic mutations that impact oncogenes and tumor suppressor genes (TSGs). Recently, growing evidence have shown that X-linked TSGs have specific role in cancer progression and metastasis as well. Interestingly, our genome harbors around substantial portion of genes that function as tumor suppressors, and the X chromosome alone harbors a considerable number of TSGs. The scenario becomes even more compelling as X-linked TSGs are adaptive to key epigenetic processes such as X chromosome inactivation. Therefore, delineating the new paradigm related to X-linked TSGs, for instance, their crosstalk with autosome and involvement in cancer initiation, progression, and metastasis becomes utmost importance. Considering this, herein, we present a comprehensive discussion of X-linked TSG dysregulation in various cancers as a consequence of genetic variations and epigenetic alterations. In addition, the dynamic role of X-linked TSGs in sex chromosome-autosome crosstalk in cancer genome remodeling is being explored thoroughly. Besides, the functional roles of ncRNAs, role of X-linked TSG in immunomodulation and in gender-based cancer disparities has also been highlighted. Overall, the focal idea of the present article is to recapitulate the findings on X-linked TSG regulation in the cancer landscape and to redefine their role toward improving cancer treatment strategies.

Unlocking the Potential of Rucaparib: A Case Series on Its Impact in Metastatic Breast Cancer With Mutations.

Triple-negative breast cancer poses distinct challenges because it lacks hormone receptors and does not have human epidermal growth factor receptor 2 (HER2) amplification. Mutations in BRCA1/2 genes are associated with homologous recombination deficiency tumors, rendering them susceptible to poly (ADP-ribose) polymerase (PARP) inhibitors. Notably, germline BRCA1/2 mutations are linked to distinct clinical features, including an increased risk of triple-negative breast cancer (TNBC) and a younger age of onset. PARP inhibitors such as olaparib and talazoparib have demonstrated efficacy in patients with BRCA mutations, leading to FDA approvals for ovarian and breast cancers. However, there remains limited data on PARP inhibitor response rates in patients with somatic BRCA mutations. This case series demonstrates the use of rucaparib in metastatic breast cancer patients harboring both germline and somatic BRCA1/2 mutations, discussing the advancing landscape of targeted therapies in breast cancer management. In the first case, despite undergoing anthracycline-based chemotherapy followed by hormonal therapy, disease progression ensued. However, transitioning to rucaparib yielded a remarkable complete response lasting over two years, highlighting its efficacy in this clinical setting. Similarly, in the second case, rucaparib demonstrated effectiveness as a maintenance therapy subsequent to achieving a near-complete response to taxane and platinum-based treatment. These findings emphasize the promising role of rucaparib in managing metastatic breast cancer in patients with BRCA1/2 mutations, further contributing to the expanding armamentarium of targeted therapies in breast cancer care.

Comparative study of reproductive and estrus characteristics of sexed and conventional semen in crossbred cows under field conditions.

Background and Aim: Sexed semen (SS), a reproductive biotechnology tool, can alter the sex ratio of offspring in bovines. This study elucidates a comparative analysis of estrus-related parameters influencing conception rate and pregnancy losses under field conditions between conventional and SS. Materials and Methods: In the present study, artificial insemination with (SS; n = 143) and conventional semen (CS; n = 143) was performed at spontaneous estrus, i.e., 16-18 h after the onset of estrus signs, to analyze their comparative evaluation in terms of conception rates in crossbred cows under field conditions. Different parameters such as age, parity, body condition score (BCS), estrus duration, inter-estrus interval (IEI), diameter of pre-ovulatory follicle (DPOF) at estrus, and cervical mucus properties (pH and spinnbarkeit [SBK]) were recorded for each cow. Results: The first insemination conception rates for sexed and conventional semen were 55.24% and 63.63% whereas the overall conception rates were 49.14% and 57.37% on days 35 and 75 post-insemination, respectively, with no significant difference (p > 0.05). Conception rates between sexed and CS inseminations were statistically significant (p < 0.01), whereas factors such as age, parity, BCS, DPOF, IEI), and SBK value exhibited no substantial variance (p > 0.05) for both types of semen straw. Conclusion: SS straws yielded a conception rate equivalent to CS straws, with estrus duration being the key factor affecting conception under field conditions.

Malaria Vector Bionomics: Countrywide Surveillance Study on Implications for Malaria Elimination in India.

BACKGROUND: The biological characteristics of mosquito vectors vary, impacting their response to control measures. Thus, having up-to-date information on vector bionomics is essential to maintain the effectiveness of existing control strategies and tools, particularly as India aims for malaria elimination by 2030. OBJECTIVE: This study aims to assess the proportions of vector species resting indoors and outdoors, determine their preference for host biting/feeding, identify transmission sites, and evaluate the susceptibility of vectors to insecticides used in public health programs. METHODS: Mosquito collections were conducted in 13 districts across 8 Indian states from 2017 to 2020 using various methods to estimate their densities. Following morphological identification in the field, sibling species of Anopheles mosquitoes were identified molecularly using polymerase chain reaction (PCR)-specific alleles. Plasmodium falciparum and Plasmodium vivax infections in the vectors were detected using enzyme-linked immunosorbent assay (ELISA) and PCR assays. In addition, we assessed the insecticide susceptibility status of primary malaria vectors following the World Health Organization (WHO) protocol. RESULTS: Anopheles culicifacies, a primary malaria vector, was collected (with a man-hour density ranging from 3.1 to 15.9) from all states of India except those in the northeastern region. Anopheles fluviatilis, another primary vector, was collected from the states of Madhya Pradesh, Maharashtra, Karnataka, and Odisha. In Haryana and Karnataka, An. culicifacies sibling species A predominated, whereas species C and E were predominant in Madhya Pradesh and Maharashtra. An. culicifacies displayed mainly endophilic behavior across all states, except in Madhya Pradesh, where the proportion of semigravid and gravid mosquitoes was nearly half of that of unfed mosquitoes. The human blood index of An. culicifacies ranged from 0.001 to 0.220 across all study sites. The sporozoite rate of An. culicifacies ranged from 0.06 to 4.24, except in Madhya Pradesh, where none of the vector mosquitoes were found to be infected with the Plasmodium parasite. In the study area, An. culicifacies exhibited resistance to DDT (dichlorodiphenyltrichloroethane; with <39% mortality). Moreover, it showed resistance to malathion (with mortality rates ranging from 49% to 78%) in all districts except Angul in Odisha and Palwal in Haryana. In addition, resistance to deltamethrin was observed in districts of Maharashtra, Gujarat, Haryana, and Karnataka. CONCLUSIONS: Our study offers vital insights into the prevalence, resting behavior, and sibling species composition of malaria vectors in India. It is evident from our findings that resistance development in An. culicifacies, the primary vector, to synthetic pyrethroids is on the rise in the country. Furthermore, the results of our study suggest a potential change in the resting behavior of An. culicifacies in Madhya Pradesh, although further studies are required to confirm this shift definitively. These findings are essential for the development of effective vector control strategies in India, aligning with the goal of malaria elimination by 2030.

CSRP1 gene: a potential novel prognostic marker in acute myeloid leukemia with implications for immune response.

BACKGROUND: Acute myeloid leukemia, constituting a majority of leukemias, grapples with a 24% 5-year survival rate. Recent strides in research have unveiled fresh targets for drug therapies. LIM-only, a pivotal transcription factor within LIM proteins, oversees cell development and is implicated in tumor formation. Among these critical LIM proteins, CSRP1, a Cysteine-rich protein, emerges as a significant player in various diseases. Despite its recognition as a potential prognostic factor and therapeutic target in various cancers, the specific link between CSRP1 and acute myeloid leukemia remains unexplored. Our previous work, identifying CSRP1 in a prognostic model for AML patients, instigates a dedicated exploration into the nuanced role of CSRP1 in acute myeloid leukemia. METHODS: R tool was conducted to analyze the public data. qPCR was applied to evaluate the expression of CSRP1 mRNA for clinical samples and cell line. Unpaired t test, Wilcoxon Rank Sum test, KM curves, spearman correlation test and Pearson correlation test were included in this study. RESULTS: CSRP1 displays notable expression variations between normal and tumor samples in acute myeloid leukemia (AML). It stands out as an independent prognostic factor for AML patients, showing correlations with clinical factors like age and cytogenetics risk. Additionally, CSRP1 correlates with immune-related pathways, immune cells, and immune checkpoints in AML. Furthermore, the alteration of CSRP1 mRNA levels is observed upon treatment with a DNMT1 inhibitor for THP1 cells. CONCLUSION: The CSRP1 has potential as a novel prognostic factor and appears to influence the immune response in acute myeloid leukemia. Additionally, there is an observed association between CSRP1 and DNA methylation in acute myeloid leukemia.

Reconstruction of Midface Defects after Radical Tumor Resection - a Rare Case Report of Solitary Fibrous Tumour of the Hard Palate.

Introduction- Spindle cell neoplasm is a variant of squamous cell carcinoma. One of its subtypes is solitary fibrous tumor. Its occurrence in head and neck is very rare and rarer in hard palate. But if occurs, radical excision is the only choice as it has malignant potential but coverage of such large mid face defects imposes a challenge in front of a Plastic Surgeon as it demands both soft tissue coverage and skeletal support. Report of the case- A 33 year male presented to our department with swelling of left side face involving the anterior palate, maxilla, nose, and upper lip. With the help of the surgical oncology team, wide local excision of the neoplasm along with bilateral infrastructure maxillectomy, total rhinectomy, total upper lip resection and total hard palatectomy was done. This created large defect in the mid face which was covered with free anterolateral thigh flap. Biopsy was done which revealed the swelling as a solitary fibrous tumor of hard palate. All the margins were free of tumour. The flap settled well. Nostrils were secured with nasal stents. After 3 months, an expander was placed in forehead of the patient for future nasal reconstruction. After 3 months, nasal reconstruction was done using expanded forehead flap and costal cartilage. After 21 days flap detachment and insetting was done. White roll creation was also done. One more secondary procedure was done for flap thinning as patient had complain of nasal obstruction. After 6 months vascularised free fibula bone graft was introduced to reconstruct maxilla for future dental rehabilitation. The patient is in regular follow up and he is satisfied with the results. Discussion- Mid face defects involving perioral and nasomaxillar areas are very uncommon and require composite reconstruction. In such cases, microvascular free flap coverage is an irreplaceable option. Multiple stages might have to be done for further refinement. Conclusion- Reconstruction after oncological resection is always very demanding. With proper preoperative planning and skilled execution, the patient can be benefited functionally, aesthetically and psychosocially.

For Malaria Elimination, India Needs to Integrate Its Research and Control Arms.

India has targeted malaria elimination by 2030. The national malaria control program has positioned its strategies in this direction. Substantial support in the form of dynamic research inputs leading to policy formulation and change is needed to steer the country towards malaria elimination. Indian Council of Medical Research (ICMR), India's nodal research body, has been generating evidence and helping to frame several policies ranging from malaria management to vector control operations. Since the country is preparing for malaria elimination, the connection between the programmatic needs and the research agenda needs further strengthening. Typically, the national malaria control program handles the implementation of programmatic activities, while the national research body, ICMR, conducts research studies to generate evidence. We propose a virtual integration of the activities conducted by these two entities to maximize the potential for translating research findings into programmatic policies. Joint monitoring of drug and insecticide resistance, codevelopment and utilization of more innovative surveillance systems, data-backed mitigation responses, and overcoming last-mile challenges are reasons for the virtual amalgamation of the two bodies. Timely translation of research outputs into policy, co-opting of workforce and material resources, joint capacity building, and synergistic advocacy are benefits of the proposed new alliance for more efficient operations. The close functioning will provide impetus to narrow down current gaps and disrupt traditional barriers, galvanizing the country toward malaria elimination.

Application of LAMP assay for detection of carbapenem-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii complex in ICU admitted sepsis patients: A rapid and cost-effective diagnostic tool.

Carbapenem-resistant significant members of Acinetobacter calcoaceticus-Acinetobacter baumannii (CR-SM-ACB) complex have emerged as an important cause of sepsis, especially in ICUs. This study demonstrates the application of loop-mediated-isothermal-amplification (LAMP) assay for detection of CR-SM-ACB-complex from patients with sepsis. Whole-blood and culture-broths(CB) collected from patients with culture-positive sepsis were subjected to LAMP and compared with PCR, and RealAmp. Vitek-2 system and conventional PCR results were used as confirmatory references. The sensitivity and specificity of LAMP(97 % & 100 %) and RealAmp(100 % & 100 %) for detection of CR-SM-ACB-complex from CB were better than PCR(87 % & 100 %). Diagnostic accuracy of LAMP, RealAmp, and PCR for detection of SM-ACB-complex from CB was 98.5 %, 100 %, and 88.5 % respectively. Turnaround time of Culture, LAMP, PCR, and RealAmp was 28-53, 6-20, 9-23, and 6-20hours, respectively. LAMP is a simple, inexpensive tool that can be applied directly to positive CB and may be customized to detect emerging pathogens and locally-prevalent resistance genes and to optimize antimicrobial use.

Initial Experience With Robotic Liver Resection in the United States.

BACKGROUND: This study's aim was to show the feasibility and safety of robotic liver resection (RLR) even without extensive experience in major laparoscopic liver resection (LLR). METHODS: A single center, retrospective analysis was performed for consecutive liver resections for solid liver tumors from 2014 to 2022. RESULTS: The analysis included 226 liver resections, comprising 127 (56.2%) open surgeries, 28 (12.4%) LLR, and 71 (31.4%) RLR. The rate of RLR increased and that of LLR decreased over time. In a comparison between propensity score matching-selected open liver resection and RLR (41:41), RLR had significantly less blood loss (384 ± 413 vs 649 ± 646 mL, P = .030) and shorter hospital stay (4.4 ± 3.0 vs 6.4 ± 3.7 days, P = .010), as well as comparable operative time (289 ± 123 vs 290 ± 132 mins, P = .954). A comparison between LLR and RLR showed comparable perioperative outcomes, even with more surgeries with higher difficulty score included in RLR (5.2 ± 2.7 vs 4.3 ± 2.5, P = .147). The analysis of the learning curve in RLR demonstrated that blood loss, conversion rate, and complication rate consistently improved over time, with the case number required to achieve the learning curve appearing to be 60 cases. CONCLUSIONS: The findings suggest that RLR is a feasible, safe, and acceptable platform for liver resection, and that the safe implementation and dissemination of RLR can be achieved without solid experience of LLR.

Robotic management of huge hepatic angiomyolipoma: A case report and literature review.

Hepatic angiomyolipoma (HAML) is a rare, benign mesenchymal liver tumor encountered in Asia, primarily in females, and can be found within the right hepatic lobe, but also in other areas of the liver. Immunohistochemically, HAMLs are characteristically positive for human melanoma black-45 antigen (HMB-45) and can histochemically vary in the composition of angiomatous, lipomatous, and myomatous tissue, together with the presence of epithelioid cells. In this case report, we discuss a previously healthy patient presenting with bloating and previously documented concern of liver lesions, found to have HAML confirmed by surgical pathology. Surgery was decided, as HAMLs greater than 10 cm are at risk of rupture. This is one of the first documented cases of HAML resected through robot-assisted bisegmentectomy and cholecystectomy, and therefore, intraoperative images have been included to assist in the planning of future robotic cases.

Utility of scores to predict alcohol use after liver transplant (lt): take them with a grain of salt.

BACKGROUND AIMS: The Sustained Alcohol use post-Liver Transplant (SALT) and the High-Risk Alcohol Relapse (HRAR) scores were developed to predict return to alcohol use after liver transplant (LT) for alcohol associated liver disease (ALD). METHODS: A retrospective analysis of deceased donor LT 10/2018 to 4/2022 was performed. All patients (pts) underwent careful pre-LT psychosocial evaluation. Data on alcohol use, substance abuse, prior rehabilitation, and legal issues were collected. Post-LT, all were encouraged to participate in rehabilitation programs and underwent interval phosphatidylethanol (PeTH) testing. Pts with ALD were stratified by < or > 6 month sobriety prior to listing. Those with <6 month were further stratified as acute alcoholic hepatitis (AH) by NIAAA criteria and non-AH. The primary outcome was utility of the SALT (<5 vs. ≥5) and HRAR (<3 vs. ≥3) scores to predict return to alcohol use (+PeTH) within 1 year after LT. RESULTS: Of the 365 LT, 86 had > 6 month sobriety and 85 had <6 month sobriety; 41 with AH and 44 non-AH. In those with AH, the mean time of abstinence to LT was 58 days, and 71% failed prior rehabilitation. Following LT, return to drinking was similar in the AH (24%) compared to <6M non-AH (15%) and >6M ALD (22%). Only 4% had returned to heavy drinking. The accuracy of both the SALT and HRAR scores to predict return to alcohol was low (accuracy 61-63%) with poor sensitivity (46% and 37%), specificity (67-68%), positive predictive value (22-26%) with moderate negative predictive value (NPV) (81-83%), respectively with higher NPVs (95%) in predicting return to heavy drinking. CONCLUSIONS: Both SALT and HRAR scores had good NPV in identifying patients at low risk for recidivism.

Bicyclic Pyrrolidine Inhibitors of Toxoplasma gondii Phenylalanine t-RNA Synthetase with Antiparasitic Potency In Vitro and Brain Exposure.

Previous studies have shown that bicyclic azetidines are potent and selective inhibitors of apicomplexan phenylalanine tRNA synthetase (PheRS), leading to parasite growth inhibition in vitro and in vivo, including in models of Toxoplasma infection. Despite these useful properties, additional optimization is required for the development of efficacious treatments of toxoplasmosis from this inhibitor series, in particular, to achieve optimal exposure in the brain. Here, we describe a series of PheRS inhibitors built on a new bicyclic pyrrolidine core scaffold designed to retain the exit-vector geometry of the isomeric bicyclic azetidine core scaffold while offering avenues to sample diverse chemical space. Relative to the parent series, bicyclic pyrrolidines retain reasonable potency and target selectivity for parasite PheRS vs host. Further structure-activity relationship studies revealed that the introduction of aliphatic groups improved potency and ADME and PK properties, including brain exposure. The identification of this new scaffold provides potential opportunities to extend the analogue series to further improve selectivity and potency and ultimately deliver a novel, efficacious treatment of toxoplasmosis.