Recent Advances in Anti-Infective Drug Discovery - Volume 16, Issue 2, 2021

Mechanism of cardiac injury in COVID-19 is a serious problem and plays critical role in mediating the severity of the disease. However, the mechanistic insights of the induction of the inflammatory signal leading to cardiac injury was poorly understood. However, few recent studies have indicated the involvement of Toll-Like Receptors (TLRs) as the major ‘culprit’ behind eliciting the initial signal of ‘cytokine storm’. As a result, TLRs are now considered as the therapeutic targets to develop efficacious therapeutics. Herein, we present an overall summary on the mechanistic insight of cardiac injury in COVID-19 patients and the therapeutic promises of TLR-targeted therapies.

Background: Dermatological disorders are cutaneous infirmities which are frequently occurring and increasing at an alarming rate. These range from mild itching/redness (dermatitis) to fatal skin cancers and has posed a major health concern. Azadirachta indica A. Juss (commonly known as neem), a member of Meliaceae family, is an Indian medicinal plant which has been known for its health promoting effects since ancient times. Objective: The review highlights the traditional practices, pharmacological aspects, and formulatory approach of neem for the treatment of dermatological disorders. Further, recent patents and novel delivery systems (developed and in pipeline) improving skin delivery and therapeutic profile of neem are discussed. Results: Neem is a traditional medicinal plant that has been employed for the prevention and treatment of numerous ailments covering systemic and topical disorders. Scientific studies have validated the traditional claims of neem and attributed these health benefits to the presence of more than 300 structurally diverse and complex compounds. It possesses anti-inflammatory, antibacterial, analgesic, antiviral, antifungal, immunomodulatory and antioxidant activities which substantiate its use as skin therapy. Various novel formulations and associated patents that improved the permeability of neem based products across skin could be found in literature. Conclusion: Critical appraisal of available literature revealed that neem possesses anti-microbial, anti-inflammatory, antioxidant and antiseptic properties. Thus it has the potential to be developed as a single effective therapy for the management of multimodal skin disorders. Further, pharmaceutical tailoring of neem by implication of novel carriers could enhance its penetrability across skin.

Aim: The study aims to prepare a class of oleanolic-based compounds. Background: Conventional drugs used to treat infectious diseases suffer from limitations such as drug toxicity and drug resistance. The resistance of microbes to antimicrobial agents is a significant challenge in treating microbial infections. Combining two or more drugs with different modes of action to treat microbial infections results in a delay in developing drug resistance by the microbes. However, it is challenging to select the appropriate drugs for combination therapy due to the differences in stability and pharmacokinetic profile of the drugs. Therefore, developing hybrid compounds using the existing drugs is a promising approach to design effective antimicrobial agents. Objectives: To prepare oleanolic-based hybrid compounds followed by characterization, in vitro antibacterial and cytotoxicity evaluation. Methods: Oleanolic acid-4-aminoquinoline-based hybrid compounds were synthesized via esterification and amidation. The compounds were characterized using FTIR, NMR, and UHPLC-HRMS. Oleanolic acid (OA) was isolated from the flower buds of Syzygium aromaticum (L.) Merr. & L.M.Perry, a species from Kingdom Plantae, order Mytales in the Myrtaceae family. Antibacterial activity was determined against selected strains of bacteria using the microdilution assay and cytotoxicity activity was assessed using the sulforhodamine B assay against selected cancer cell lines. Results: The synthesized hybrid compounds exhibited antibacterial activity against the Gram-positive bacteria Enterococcus faecalis (ATCC13047), Bacillus subtilis (ATCC19659), Staphylococcus aureus as well as Gram-negative bacteria, Klebsiella oxytoca (ATCC8724), Escherischia coli (ATCC25922), and Proteus vulgaris (ATCC6380) with minimum inhibitory concentrations of 1.25 mg/mL compared to oleanolic acid (2.5 mg/mL). Compounds 13 and 14 displayed cytotoxicity in vitro against the cancer cell lines (MCF-7 and DU 145) compared to the oleanolic acid (IC50 #131; 200 μM). Conclusion: Modification of C28 of OA enhanced its biological activity.

Introduction: Onychomycosis, also called tinea unguium, is a common fungal infection affecting the nails. After dermatophytes, Candida species are recognized as second-line pathogens responsible for this infection. The treatment of onychomycosis requires a long time and is associated with high rates of recurrence. Antifungal medicines conjugated with gold (Au-NP) nanoparticle are the possible platforms for the reduction of drug resistance. Methods: In the present study, we reported the in-vitro antifungal activity of itraconazole (ITZ) – Au conjugates, time-kill studies, and biofilm-producing ability of six ITZ-resistant C. glabrata. Results: 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium bromide (MTT) quantitative results revealed that four out of six resistant isolates studied able to form biofilms in vitro. ITZ-Au conjugates were more effective than ITZ or Au nanoparticle alone, and the time-kill tests pointed to the suitable effect of ITZ-Au conjugate. Conclusion: The present study concluded that ITZ-Au conjugates have an inhibitory effect on the biofilm of resistant C. glabrata isolates. Further studies are needed to compare the ex-vivo onychomycosis model.

Introduction: Metallo-β-lactamases (MBLs) play a major role in the resistance of Pseudomonas aeruginosa to carbapenems. We investigated the antibiotic susceptibility patterns and frequency of MBLs genes (blaIMP and blaSPM) in carbapenem-resistant P. aeruginosa clinical isolates in Sari, Iran. Materials and Methods: The isolates were identified using standard microbiological tests, and their antibiotic susceptibility pattern was determined by the disk agar diffusion method according CLSI criteria. Phenotypic identification of MBL-producing strains assessed by the combined disk test (CDT). Then, polymerase chain reaction (PCR) was used to detect the presence of blaIMP and blaSPM genes. Results: The highest and lowest levels of antibiotic resistance were observed against gentamicin (40%) and piperacillin-tazobactam (13%), respectively. Besides, 40 isolates (40%) had the multi-drug resistant (MDR) phenotype, while 5 (12.5%) MDR isolates were resistant to all antibiotics tested. The results of the CDT showed that among 43 carbapenem non-susceptible clinical isolates of P. aeruginosa, 33 (76.74%) isolates were MBL-producing strains. Also, the frequency of the blaIMP gene among 43 carbapenem non susceptible isolates was determined to be 6.97%, while none of these isolates carried the blaSPM gene. Conclusion: Due to the high prevalence of carbapenem-resistant and MDR P. aeruginosa in this study, routine antibiotic susceptibility testing and phenotypic identification of carbapenemase production by this bacterium are necessary for the proper selection of antibiotics.

Background & Aims: There is high proportion of geriatric patients who acquired chronic hepatitis C virus infection. There is a shortage in evidence- based data as regards direct-acting antivirals in this group of patients. The aim was to assess safety, efficacy, and tolerability of direct acting antiviral drugs in Egyptian geriatric patients. Methods: This prospective study was performed on 177 patients with chronic hepatitis C and administrated different regimens of direct acting antivirals. Patients were divided into two groups: Group I: patients below 65 years old (N = 143), and Group II: patients > 65 years old (N = 34). Pretreatment history taking, baseline characteristics, and investigations were done for both groups. Follow up was made to detect treatment efficacy and adverse effects. Results: Geriatric group were found to have more comorbidities (diabetes mellitus, hypertension, and cardiomyopathy); also liver cirrhosis. Minor adverse effects occurred in both groups without significant difference included fatigue, insomnia, headache, and dizziness. Vomiting, diarrhea, and skin rash occurred in group II more than group I. Leucopenia, thrombocytopenia, jaundice, and significant anemia occurred without significant difference between both groups. Eighteen patients (25%) of 72 patients who took ribavirin had to reduce ribavirin dose or to stop it. The overall treatment response in the entire study was 97.7% without significant difference between both groups. Conclusion: Direct acting antivirals are recommended regardless the age. These drugs are effective and tolerable in elderly patients. Attention to other comorbidities, drug-drug interactions, and follow up are recommended.

Background: In the past few centuries, a widespread increase in antimicrobial resistance has been observed among Klebsiella species. The antibiotic- resistant strains of the genus Klebsiella are becoming a serious threat in clinical settings due to their involvement in severe invasive and non-invasive infections. The emergence of resistance among these strains is associated with their strong enzymatic activity against several broad-spectrum antibiotics. These enzymes include beta-lactamases, extended-spectrum beta-lactamases (ESBL), AmpC beta-lactamases, and carbapenemases. These resistance enzymes are capable of hydrolyzing various broad-spectrum drugs like extended-spectrum cephalosporin and carbapenems. Objective: The present study was conducted to determine the emerging resistance among Klebsiella strains by identifying the production of carbapenemase enzyme phenotypically and the frequency of the NDM resistance gene by a polymerase chain reaction. Methods: In this study, 236 Gram-negative isolates from different clinical laboratories were identified. Out of which, 125 isolates were found as Klebsiella species by using standard microbiological techniques. Minimum inhibitory concentrations (MIC) were determined using eight representative antibiotics by the Macro broth dilution method. Phenotypic detection of carbapenemase producing Klebsiella species was performed by Modified Hodge Test. Phenotypic findings were then checked and compared with genotypic results obtained by using the Polymerase chain reaction (PCR) for the detection of resistance genes responsible for the production of carbapenemase. Results: In this study, carbapenemase production was found only in 6 (5%) Klebsiella isolates by using the phenotypic method; however, 3 isolates out of 125 were screened positive for the gene NDM-1. Conclusion: Since we are considering carbapenems as the last therapeutic option for treating infections, mainly caused by Gram-negative isolates, the prevailing resistance against this drug is widely disseminating. It is better to evaluate the antibiotic susceptibility, phenotypic screening as well genotypic screening (where possible) for implementing strict antibiotic control policies in health care settings, hospitals, laboratories, etc.

The authors wish to add words “Research Scholar” and “Research Supervisor” to their affiliations [1]. The original article can be found online at https://doi.org/10.2174/1574891X15999201110212725 The corrected affiliation is: 1Department of Pharmaceutics, Rayat-Bahra College of Pharmacy, Hoshiarpur, Punjab 146001, India; 2Faculty of Pharma-ceutical Sciences, Department of Pharmaceutics, PCTE Group of Institutes, Ludhiana, Punjab 142021, India; 3Research Scholar, I.K. Gujral Punjab Technical University, Jalandhar-Punjab 144601, India; 4Research Supervisor, I.K. Gujral Punjab Technical University, Jalandhar-Punjab 144601, India