Coordination Complexes to Combat Bacterial Infections: Recent Developments, Current Directions and Future Opportunities.

Drug discovery aimed at the efficient eradication of life-threatening bacterial infections, especially in light of the emergence of multi-drug resistance of pathogenic bacteria, has remained a challenge for medicinal chemists over the past several decades. As nutrient acquisition and metabolism at the host-pathogen interface become better elucidated, new drug targets continue to emerge. Metal homeostasis is among these processes, and thus provides opportunities for medicinal inorganic chemists to alter or disrupt these processes selectively to impart bacteriostatic or bacteriotoxic effects. In this minireview, we showcase some of the recent work from the field of metal-based antibacterial agents and highlight divergent strategies and mechanisms of action.

Clinical Outcomes With Abemaciclib After Prior CDK4/6 Inhibitor Progression in Breast Cancer: A Multicenter Experience.

BACKGROUND: Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are widely used as first-line therapy for hormone receptor-positive metastatic breast cancer (HR+ MBC). Although abemaciclib monotherapy is also FDA-approved for treatment of disease progression on endocrine therapy, there is limited insight into the clinical activity of abemaciclib after progression on prior CDK4/6i. PATIENTS AND METHODS: We identified patients with HR+ MBC from 6 cancer centers in the United States who received abemaciclib after disease progression on prior CDK4/6i, and abstracted clinical features, outcomes, toxicity, and predictive biomarkers. RESULTS: In the multicenter cohort, abemaciclib was well tolerated after a prior course of CDK4/6i (palbociclib)-based therapy; a minority of patients discontinued abemaciclib because of toxicity without progression (9.2%). After progression on palbociclib, most patients (71.3%) received nonsequential therapy with abemaciclib (with ≥1 intervening non-CDK4/6i regimens), with most receiving abemaciclib with an antiestrogen agent (fulvestrant, 47.1%; aromatase inhibitor, 27.6%), and the remainder receiving abemaciclib monotherapy (19.5%). Median progression-free survival for abemaciclib in this population was 5.3 months and median overall survival was 17.2 months, notably similar to results obtained in the MONARCH-1 study of abemaciclib monotherapy in heavily pretreated HR+/HER2-negative CDK4/6i-naïve patients. A total of 36.8% of patients received abemaciclib for ≥6 months. There was no relationship between the duration of clinical benefit while on palbociclib and the subsequent duration of treatment with abemaciclib. RB1, ERBB2, and CCNE1 alterations were noted among patients with rapid progression on abemaciclib. CONCLUSIONS: A subset of patients with HR+ MBC continue to derive clinical benefit from abemaciclib after progression on prior palbociclib. These results highlight the need for future studies to confirm molecular predictors of cross-resistance to CDK4/6i therapy and to better characterize the utility of abemaciclib after disease progression on prior CDK4/6i.

General Approach to Direct Measurement of the Hydration State of Coordination Complexes in the Gas Phase: Variable Temperature Mass Spectrometry.

The formation of ternary aqua complexes of metal-based diagnostics and therapeutics is closely correlated to their in vivo efficacy but approaches to quantify the presence of coordinated water ligands are limited. We introduce a general and high-throughput method for characterizing the hydration state of para- and diamagnetic coordination complexes in the gas phase based on variable-temperature ion trap tandem mass spectrometry. Ternary aqua complexes are directly observed in the mass spectrum and quantified as a function of ion trap temperature. We recover expected periodic trends for hydration across the lanthanides and distinguish complexes with several inner-sphere water ligands by inspection of temperature-dependent speciation curves. We derive gas-phase thermodynamic parameters for discernible inner- and second-sphere hydration events, and discuss their application to predict solution-phase behavior. The differences in temperature at which water binds in the inner and outer spheres arise primarily from entropic effects. The broad applicability of this method allows us to estimate the hydration states of Ga, Sc, and Zr complexes under active preclinical and clinical study with as-yet undetermined hydration number. Variable-temperature mass spectrometry emerges as a general tool to characterize and quantitate trends in inner-sphere hydration across the periodic table.

Imaging the Granzyme Mediated Host Immune Response to Viral and Bacterial Pathogens In Vivo Using Positron Emission Tomography.

Understanding how the host immune system engages complex pathogens is essential to developing therapeutic strategies to overcome their virulence. While granzymes are well understood to trigger apoptosis in infected host cells or bacteria, less is known about how the immune system mobilizes individual granzyme species in vivo to combat diverse pathogens. Toward the goal of studying individual granzyme function directly in vivo, we previously developed a new class of radiopharmaceuticals termed "restricted interaction peptides (RIPs)" that detect biochemically active endoproteases using positron emission tomography (PET). In this study, we showed that secreted granzyme B proteolysis in response to diverse viral and bacterial pathogens could be imaged with [64Cu]Cu-GRIP B, a RIP that specifically targets granzyme B. Wild-type or germline granzyme B knockout mice were instilled intranasally with the A/PR/8/34 H1N1 influenza A strain to generate pneumonia, and granzyme B production within the lungs was measured using [64Cu]Cu-GRIP B PET/CT. Murine myositis models of acute bacterial (E. coli, P. aeruginosa, K. pneumoniae, and L. monocytogenes) infection were also developed and imaged using [64Cu]Cu-GRIP B. In all cases, the mice were studied in vivo using mPET/CT and ex vivo via tissue-harvesting, gamma counting, and immunohistochemistry. [64Cu]Cu-GRIP B uptake was significantly higher in the lungs of wild-type mice that received A/PR/8/34 H1N1 influenza A strain compared to mice that received sham or granzyme B knockout mice that received either treatment. In wild-type mice, [64Cu]Cu-GRIP B uptake was significantly higher in the infected triceps muscle versus normal muscle and the contralateral triceps inoculated with heat killed bacteria. In granzyme B knockout mice, [64Cu]Cu-GRIP B uptake above the background was not observed in the infected triceps muscle. Interestingly, live L. monocytogenes did not induce detectable granzyme B on PET, despite prior in vitro data, suggesting a role for granzyme B in suppressing their pathogenicity. In summary, these data show that the granzyme response elicited by diverse human pathogens can be imaged using PET. These results and data generated via additional RIPs specific for other granzyme proteases will allow for a deeper mechanistic study analysis of their complex in vivo biology.

A Gene Panel Associated With Abemaciclib Utility in ESR1-Mutated Breast Cancer After Prior Cyclin-Dependent Kinase 4/6-Inhibitor Progression.

PURPOSE: For patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), first-line treatment is endocrine therapy (ET) plus cyclin-dependent kinase 4/6 inhibition (CDK4/6i). After disease progression, which often comes with ESR1 resistance mutations (ESR1-MUT), which therapies to use next and for which patients are open questions. An active area of exploration is treatment with further CDK4/6i, particularly abemaciclib, which has distinct pharmacokinetic and pharmacodynamic properties compared with the other approved CDK4/6 inhibitors, palbociclib and ribociclib. We investigated a gene panel to prognosticate abemaciclib susceptibility in patients with ESR1-MUT MBC after palbociclib progression. METHODS: We examined a multicenter retrospective cohort of patients with ESR1-MUT MBC who received abemaciclib after disease progression on ET plus palbociclib. We generated a panel of CDK4/6i resistance genes and compared abemaciclib progression-free survival (PFS) in patients without versus with mutations in this panel (CDKi-R[-] v CDKi-R[+]). We studied how ESR1-MUT and CDKi-R mutations affect abemaciclib sensitivity of immortalized breast cancer cells and patient-derived circulating tumor cell lines in culture. RESULTS: In ESR1-MUT MBC with disease progression on ET plus palbociclib, the median PFS was 7.0 months for CDKi-R(-) (n = 17) versus 3.5 months for CDKi-R(+) (n = 11), with a hazard ratio of 2.8 (P = .03). In vitro, CDKi-R alterations but not ESR1-MUT induced abemaciclib resistance in immortalized breast cancer cells and were associated with resistance in circulating tumor cells. CONCLUSION: For ESR1-MUT MBC with resistance to ET and palbociclib, PFS on abemaciclib is longer for patients with CDKi-R(-) than CDKi-R(+). Although a small and retrospective data set, this is the first demonstration of a genomic panel associated with abemaciclib sensitivity in the postpalbociclib setting. Future directions include testing and improving this panel in additional data sets, to guide therapy selection for patients with HR+/HER2- MBC.

Tracking Uptake and Metabolism of Xenometallomycins Using a Multi-Isotope Tagging Strategy.

Synthetic and naturally occurring siderophores and their conjugates provide access to the bacterial cytoplasm via active membrane transport. Previously, we displaced iron with the radioactive isotope 67Ga to quantify and track in vitro and in vivo uptake and distribution of siderophore Trojan Horse antibiotic conjugates. Here, we introduce a multi-isotope tagging strategy to individually elucidate the fate of metal cargo and the ligand construct with radioisotopes 67Ga and 124I. We synthesized gallium(III) model complexes of a ciprofloxacin-functionalized linear desferrichrome (Ga-D6) and deferoxamine (Ga-D7) incorporating an iodo-tyrosine linker to enable radiolabeling using the metal-binding (67Ga) and the cargo-conjugation site (124I). Radiochemical experiments with Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa wt strains show that 67Ga-D6/D7 and Ga-D6-124I/D7-124I have comparable uptake, indicating intact complex import and siderophore-mediated uptake. In naive mice, 67Ga-D6/D7 and Ga-D6-124I/D7-124I demonstrate predominantly renal clearance; urine metabolite analysis indicates in vivo dissociation of Ga(III) is a likely mechanism of degradation for 67Ga-D6/D7 when compared to ligand radiolabeled compounds, Ga-D6-124I/D7-124I, which remain >60% intact in urine. Cumulatively, this work demonstrates that a multi-isotope tagging strategy effectively elucidates the in vitro uptake, pharmacokinetics, and in vivo stability of xenometallomycins with modular chemical structures.

45Ti targeted tracers for PET imaging of PSMA.

PURPOSE: Positron Emission Tomography is an important molecular imaging technique for detection and diagnoses of various disease states. This work aims to develop novel titanium-45 (t½ = 3.08 h) PET tracers using Prostate Specific Membrane Antigen (PSMA) targeting vectors for imaging of prostate cancer as proof of concept for this relatively unexplored isotope. PROCEDURES: Titanium-45 was produced on the University of Alabama at Birmingham (UAB) TR24 cyclotron using proton bombardments on natural scandium foils and separated using procedures described previously [1]. After purification, Titanium-45 was used to radiolabel two PSMA-targeting molecules; DFO-DUPA and LDFC-DUPA. Radiochemical yields were determined via radio-high purity liquid chromatography (radioHPLC). The radiolabeled compounds were tested both in vitro and in vivo using PSMA+ cell lines (LNCaP and 22Rv1) and PSMA- cell lines (PC3). RESULTS: Titanium-45 was produced and purified in yields suitable for research studies. Radiochemical yields of up to 98 ± 1% were achieved with DFO-DUPA and 92 ± 7% with LDFC-DUPA. PSMA specific targeting was observed in vitro in PSMA positive cells (LNCaP (0.6% ± 0.05%) and confirmed by blocking (0.15% ± 0.04%) (P < 0.0001)), compared to uptake in the PSMA negative cells (PC3 (0.07% ± 0.008%)) and confirmed by blocking (0.07% ± 0.01%) (P = 0.5253). In vivo studies demonstrated statistically significant uptake in LNCaP tumors (2.3% ± 0.3% ID/g) compared to PC3 tumor uptake (0.1% ± 0.07%). CONCLUSIONS: This work shows that titanium-45 can be used to radiolabel PSMA targeting compounds with high radiochemical yields. These radiolabeled compounds remain intact in serum for at least two half-lives of titanium-45, showing that these compounds would be appropriate for implementation in the clinical setting. This study shows the feasibility of using titanium-45 as positron emitting radiometal for use in imaging PSMA+ prostate cancer, and illustrates that further research is in this area is warranted.

Galbofloxacin: a xenometal-antibiotic with potent in vitro and in vivo efficacy against S. aureus.

Siderophore-antibiotic drug conjugates are considered potent tools to deliver and potentiate the antibacterial activity of antibiotics, but only few have seen preclinical and clinical success. Here, we introduce the gallium(iii) complex of a ciprofloxacin-functionalized linear desferrichrome, Galbofloxacin, with a cleavable serine linker as a potent therapeutic for S. aureus bacterial infections. We employed characterization using in vitro inhibitory assays, radiochemical, tracer-based uptake and pharmacokinetic assessment of our lead compound, culminating in in vivo efficacy studies in a soft tissue model of infection. Galbofloxacin exhibits a minimum inhibitory concentration of (MIC98) 93 nM in wt S. aureus, exceeding the potency of the parent antibiotic ciprofloxacin (0.9 µM). Galbofloxacin is a protease substrate that can release the antibiotic payload in the bacterial cytoplasm. Radiochemical experiments with wt bacterial strains reveal that 67Galbofloxacin is taken up efficiently using siderophore mediated, active uptake. Biodistribution of 67Galbofloxacin in a mouse model of intramuscular S. aureus infection revealed renal clearance and enhanced uptake in infected muscle when compared to 67Ga-citrate, which showed no selectivity. A subsequent in vivo drug therapy study reveals efficient reduction in S. aureus infection burden and sustained survival with Galbofloxacin for 7 days. Ciprofloxacin had no treatment efficacy at identical molecular dose (9.3 µmol kg-1) and resulted in death of all study animals in <24 hours. Taken together, the favorable bacterial growth inhibitory, pharmacokinetic and in vivo efficacy properties qualify Galbofloxacin as the first rationally designed Ga-coordination complex for the management of S. aureus bacterial infections.

Management Practices and Predictors of Outcome of Liver Abscess in Adults: A Series of 1630 Patients from a Liver Unit.

BACKGROUND: The management practices of liver abscess (LA) have evolved over time. The precise diagnosis of etiology and complications is pivotal for appropriate management. METHODS: Descriptive analyses of consecutive patients treated for LA using electronic medical records at a liver unit between years 2010 and 2020 and investigate relationships between clinical, imaging, laboratory and microbiological findings, treatment strategies and mortality. RESULTS: Of 1630 LA patients, the most common aetiologies were amoebic liver abscess (ALA; 81%) and pyogenic liver abscess (PLA; 10.3%, mainly related to biliary disease and/or obstruction). Abdominal pain (86%) and fever (85.3%) were the commonest presenting symptoms (median duration-10 days). Almost 10% had jaundice at presentation, 31.1% were diabetic, 35.5% had chronic alcohol use and 3.3% had liver cirrhosis. Nearly 54% LA were solitary, 77.7% localized to the right liver lobe (most commonly segment VII/VIII). Patients with large LA (>10 cm, 11.9%) had more frequent jaundice and abscess rupture (p-0.01). Compared with ALA, patients with PLA were older, more often had multiple and bilobar abscesses with local complications. Over four-fifth of the patients received percutaneous interventions (catheter drainage [PCD; 36.1%] alone and needle aspiration [PNA] plus PCD [34.1%] as most common). Fifty-eight patients underwent endoscopic retrograde cholangiography for intrabiliary abscess rupture (n = 36) or cholangitic abscess (n = 22). The median duration of hospital stay and PCD were 7 (4-10) days and 5 (4-8 days), respectively. The overall in-hospital mortality was 1.1%. Presence of septic encephalopathy (HR: 20.8; 95% CI: 1.9-220.7; p-0.012), liver cirrhosis (HR: 20.1; 95% CI: 2.7-146.9; p-0.003) and jaundice (HR: 7.6; 95% CI:1.7-33.1; p-0.006) were independent predictors of mortality. CONCLUSIONS: The commonest presentation was middle age male with right lobe solitary ALA. Patients with large, bilobar and/or pyogenic abscess had more complications. Nearly 70% patients require percutaneous interventions, which if given early improve treatment outcomes. Presence of jaundice, liver cirrhosis and septic encephalopathy were independent predictors of mortality.

Coronavirus disease (COVID-19): A systematic review and meta-analysis to evaluate the impact of various comorbidities on serious events.

BACKGROUND AND AIMS: Currently there is limited knowledge on medical comorbidities and COVID-19; we conducted a systematic review and meta-analysis to evaluate the impact of various morbidities on serious events in COVID 19. METHODS: PubMed, Cochrane Central Register of Clinical Trials were searched on April 28, 2020, to extract published articles that reported the outcomes of COVID-19 patients. The search terms were "coronavirus" and "clinical characteristics". ICU admission, mechanical ventilation, ARDS, Pneumonia, death was considered serious events. The comorbidities assessed in the study were Hypertension (HTN), Diabetes mellitus (DM), Cardiovascular diseases (CVD), Chronic obstructive pulmonary disease (COPD) and Chronic Kidney disease (CKD). Subsequently, comparisons between comorbidity patient group and the non-comorbidity patient groups, in terms of serious events were made using the pooled estimates of odd's ratio (OR) RESULTS: We identified 688 published results and 16 studies with 3994 patients were included in the systematic review. Serious events were seen in 526(13.16%) patients. Presence of hypertension with OR 2.95, diabetes mellitus with OR 3.07, Cardio vascular disease with OR 4.58, COPD with OR 6.66 and Chronic kidney disease with OR 5.32 had significant association in patients with COVID 19 on having serious events. Presence of diabetes mellitus (OR 2.78)) had a significant impact on death in COVID 19 patients with a p-value 0.004. CONCLUSIONS: Presence of medical comorbidities in COVID-19 leads to higher risk of developing serious events i.e. ICU admission, mechanical intubation and mortality. The presence of Diabetes mellitus has a significant impact on mortality rate in COVID-19 patients.

Focus on uncommon symptoms of COVID-19: Potential reason for spread of infection.

Focus on uncommon symptoms of COVID-19: Potential reason for spread of infection.

A Salmochelin S4-Inspired Ciprofloxacin Trojan Horse Conjugate.

A novel ciprofloxacin-siderophore Trojan Horse antimicrobial was prepared by incorporating key design features of salmochelin, a stealth siderophore that evades mammalian siderocalin capture via its glycosylated catechol units. Assessment of the antimicrobial activity of the conjugate revealed that attachment of the salmochelin mimic resulted in decreased potency, compared to ciprofloxacin, against two Escherichia coli strains, K12 and Nissle 1917, in both iron replete and deplete conditions. This observation could be attributed to a combination of reduced DNA gyrase inhibition, as confirmed by in vitro DNA gyrase assays, and reduced bacterial uptake. Uptake was monitored using radiolabeling with iron-mimetic 67Ga3+, which revealed limited cellular uptake in E. coli K12. In contrast, previously reported staphyloferrin-based conjugates displayed a measurable uptake in analogous 67Ga3+ labeling studies. These results suggest that, in the design of Trojan Horse antimicrobials, the choice of siderophore and the nature and length of the linker remain a significant challenge.

Impact of COVID -19 in cancer patients on severity of disease and fatal outcomes: A systematic review and meta-analysis.

BACKGROUND AND AIMSBACKGROUND: Currently there is limited knowledge on cancer and COVID-19; we conducted a systematic review and meta-analysis to evaluate the impact of cancer on serious events including ICU admission rate and mortality in COVID 19. METHODS: PubMed, Cochrane Central Register of Clinical Trials were searched on April 16, 2020, to extract published articles that reported the outcomes of cancer in COVID-19 patients. The search terms were "coronavirus" and "clinical characteristics" with no language or time restrictions. We identified 512 published results and 13 studies were included in the analysis. RESULTS: There were 3775 patients, of whom 63 (1·66%) had a cancer. The pooled estimates of ICU admission in COVID 19 patients with and without cancer were 40% versus 8·42%.The odds ratio of ICU admission rates between the cancer and non-cancer groups was 2.88 with a 95% CI of 1·18 to 7·01 (p = 0·026). The pooled estimates of death rate in COVID -19 patients with and without cancer were 20·83% versus 7·82%. The odds ratio of death rates between the cancer and non-cancer groups was 2.25 with a 95% CI ranging from 0·71 to 7·10 with p value of 0·166. The pooled prevalence of cancer patients was 2% (95 CI 1-4). CONCLUSIONS: Presence of cancer in COVID-19 leads to higher risk of developing serious events i.e. ICU admission, mechanical ventilation and mortality. The presence of cancer has a significant impact on mortality rate in COVID-19 patients.

No benefit of hydroxychloroquine in COVID-19: Results of Systematic Review and Meta-Analysis of Randomized Controlled Trials".

BACKGROUND AND AIMS: Coronavirus pandemic is currently a global public health emergency with no definitive treatment guidelines. We conducted a systematic review and meta-analysis of the literature evaluating the efficacy of hydroxychloroquine and its related formulations in COVID-19 patients. METHODS: A systematic search of PubMed, Scopus, MedRxiv data and Cochrane Central Register of Clinical Trials for published articles that reported the outcomes of COVID-19 patients treated with hydroxychloroquine or its compounds was done. We identified 1071 published studies and 7 studies were included in the analysis. RESULTS: The study population consisted of a total of 4984 patients, of which 1721 (34.5%) received hydroxychloroquine or its congeners (HCQ group) while 3091 (62.01%) received standard of care or had included antiviral medication (control group). The pooled estimate of successful treatment in the hydroxychloroquine group and the control group was 77.45% and 77.87% respectively, which indicated similar clinical outcomes in patients treated with hydroxychloroquine compared to the control group. The odds ratio of a favourable outcome with hydroxychloroquine was 1.11 (95 CI 0.72 to 1.69) (p = 0.20). The pooled risk difference of favourable outcome with hydroxychloroquine versus control group was 0.00 (95 CI -0.03 to 0.03) which was statistically not significant (p = 0.10). CONCLUSIONS: The present evidence shows no benefit of hydroxychloroquine in patients affected by mild to moderate COVID-19 disease. However, now several trials on HCQ are ongoing and hopefully more data will be available soon. Hence, the management of COVID-19 is set to change for better in the future.

Theranostic Gallium Siderophore Ciprofloxacin Conjugate with Broad Spectrum Antibiotic Potency.

Pathogenic bacteria scavenge ferric iron from the host for survival and proliferation using small-molecular chelators, siderophores. Here, we introduce and assess the gallium(III) complex of ciprofloxacin-functionalized desferrichrome (D2) as a potential therapeutic for bacterial infection using an in vitro assay and radiochemical, tracer-based approach. Ga-D2 exhibits a minimum inhibitory concentration of 0.23 µM in Escherichia coli, in line with the parent fluoroquinolone antibiotic. Competitive and mutant strain assays show that Ga-D2 relies on FhuA-mediated transport for internalization. Ga-D2 is potent against Pseudomonas aeruginosa (3.8 µM), Staphylococcus aureus (0.94 µM), and Klebsiella pneumoniae (12.5 µM), while Fe-D2 is inactive in these strains. Radiochemical experiments with E. coli reveal that 67Ga-D2 is taken up more efficiently than 67Ga-citrate. In naive mice, 67Ga-D2 clears renally and is excreted 13% intact in the urine. These pharmacokinetic and bacterial growth inhibitory properties qualify Ga-D2 for future investigations as a diagnosis and treatment tool for infection.

Preclinical evaluation and molecular docking of 1,3-benzodioxole propargyl ether derivatives as novel inhibitor for combating the histone deacetylase enzyme in cancer.

Even after huge strides in medicine, cancer continues to be a formidable disease, which is slated to become the leading cause of death worldwide. The present study investigates the 1,3-benzodioxole and its propargyl ether derivatives as a novel histone deacetylase enzyme inhibitor in order to cure cancer, as aberrant expression of histone deacetylases (HDACs) is associated with carcinogenesis. Bioinformatics approaches were employed to carry out preclinical and pharmacological evaluations of designed benzodioxole derivatives. Furthermore, their interaction with HDAC-1 enzyme was studied through computational methods for their specific inhibitory effects and evaluated for their LD50 (oral rat acute toxicity) value. In addition to this work, three-dimensional (3D) structure of HDAC-1 enzyme was extracted and evaluated using various parameters including Ramachandran plot and molecular docking stimulation. In our study, we found that compound 7 and compound 9 have higher binding score than approved drugs (SAHA, TSA and VPA). Importantly, these compounds were found to possess good pharmacological and pharmacokinetic properties and can be considered as potent novel compound to combat the HDAC-1 enzyme to cure cancer. Compounds were also analyzed and validated with parameters like absorption, metabolism, excretion, toxicity and synthetic accessibility during the preclinical evaluation. This study paves way to search for novel and potent small chemical compounds for inhibiting HDAC-1 enzyme and in particular to combat the cancer progression by interrupting the cell cycle.

Comparative Evaluation of Enhancing Retention of Dislodged Crowns Using Preparation Modifications and Luting Cements: An In-Vitro Study.

BACKGROUND: Complete cast crowns are good alternatives and have best longevity for the restoration of damaged posterior teeth. Occasionally, a crown with clinically acceptable margins, preparation design, and occlusion becomes loose. Providers often debate whether such a crown can be successfully recemented with any degree of confidence that it will not be dislodged under normal masticatory function. It has been documented that resistance form increases by placing grooves opposing each other in a crown and tooth; cements also have a role to play in retention of crowns. To determine whether the addition of horizontal groove in the internal surface of the crown and/or tooth preparation will increase retention of the crowns, without remaking them and achieving better retention with cements. MATERIALS AND METHODS: A total of 80 extracted human mandibular molars were taken and standard preparation was done. After the crowns were ready, the groove was made in the internal surface of the crown and on the tooth, which were cemented with glass ionomer cement and resin cement. The tensile force needed to dislodge the crowns and teeth after cementation was found out. RESULT: The mean tensile force needed to dislodge the crown and tooth combination was highest for the group in which crown had a groove without any groove on the tooth and cemented using resin cement (252.60N). CONCLUSION: It can be concluded from the study that it is best to recement a crown and tooth combination using resin cement where the crown has a groove, and the tooth has no groove.