Sandeep Lohan

Tea: A native source of antimicrobial agents

Abstract Tea (Camellia sinensis) is one of the most popular nonalcoholic beverages, consumed by over two-thirds of the worlds population because of its refreshing, mild stimulant and medicinal properties. It is processed in different ways in different parts of the world to give green, black, oolong, and pu-erh tea. Among all tea polyphenols, epigallocatechin-3-gallate has been responsible for much of the health promoting abilities of tea including anti-inflammatory, antimicrobial, antitumour, anti-oxidative, protection from cardiovascular disease, anti-obesity, and anti-aging properties. In the present review, the antibacterial, antiviral, and antifungal activities of different types of tea and their polyphenols are reported, highlighting their mechanisms of action and structure–activity relationship. Moreover, considering that the changing patterns of infectious diseases and the emergence of microbial strains resistant to current antibiotics, there is an urgent need to find out new potent antimicrobial agents as adjuvants to antibiotic therapy. The synergistic effect of tea polyphenols in combination with conventional antimicrobial agents against clinical multidrug-resistant microorganisms has also been discussed in this review.

Recent approaches in design of peptidomimetics for antimicrobial drug discovery research.

Resistant pathogenic microbial strains are emerging at a rate that far exceeds the pace of new anti-infective drug development. In order to combat resistance development, there is pressing need to develop novel class of antibiotics having different mechanism of action in comparison to existing antibiotics. Antimicrobial peptides (AMPs) have been identified as ubiquitous components of innate immune system and widely regarded as a potential source of future antibiotics owing to a remarkable set of advantageous properties ranging from broad spectrum of activity to low propensity of resistance development. However, AMPs present several drawbacks that strongly limit their clinical applicability as ideal drug candidates such as; poor bioavailability, potential immunogenicity and high production cost. Thus, to overcome the limitations of native peptides, peptidomimetic becomes an important and promising approach. The different research groups worldwide engaged in antimicrobial drug discovery over the past decade have paid tremendous effort to design peptidomimetics. This review will focus on recent approaches in design of antimicrobial peptidomimetics their structure-activity relationship studies, mode of action, selectivity & toxicity.

Quantitative structure-activity relationship (QSAR) studies as strategic approach in drug discovery

Drug design is a process which is driven by technological breakthroughs implying advanced experimental and computational methods. Nowadays, the techniques or the drug design methods are of paramount importance for prediction of biological profile, identification of hits, generation of leads, and moreover to accelerate the optimization of leads into drug candidates. Quantitative structure–activity relationship (QSAR) has served as a valuable predictive tool in the design of pharmaceuticals and agrochemicals. From decades to recent research, QSAR methods have been applied in the development of relationship between properties of chemical substances and their biological activities to obtain a reliable statistical model for prediction of the activities of new chemical entities. Classical QSAR studies include ligands with their binding sites, inhibition constants, rate constants, and other biological end points, in addition molecular to properties such as lipophilicity, polarizability, electronic, and steric properties or with certain structural features. 3D-QSAR has emerged as a natural extension to the classical Hansch and Free–Wilson approaches, which exploit the three-dimensional properties of the ligands to predict their biological activities using robust chemometric techniques such as PLS, G/PLS, and ANN. This paper provides an overview of 1-6 dimension-based developed QSAR methods and their approaches. In particular, we present various dimensional QSAR approaches, such as comparative molecular field analysis (CoMFA), comparative molecular similarity analysis, Topomer CoMFA, self-organizing molecular field analysis, comparative molecule/pseudo receptor interaction analysis, comparative molecular active site analysis, and FLUFF-BALL, 4D-QSAR, and G-QSAR approaches.

Systematic Study of Non‐Natural Short Cationic Lipopeptides as Novel Broad‐Spectrum Antimicrobial Agents

We describe the design and synthesis of a new series of non‐natural short cationic lipopeptides (MW = 700) as antimicrobial agents. All of the synthesized lipopeptides were tested against a range of microbes such as Gram‐positive, Gram‐negative bacteria, fungi including methicillin‐resistant Staphylococcus aureus (MRSA) and methicillin‐resistant Staphylococcus epidermidis (MRSE). By systematic study of design template, we found that three ornithine residues conjugated with myristic acid are minimum requirement for a compound to be an antimicrobial agent. The most potent lipopeptide LP16 possesses broad‐spectrum antimicrobial activity and has MICs in the range of 1.5–6.25 μg/mL against Escherichia coli, S. aureus, Pseudomonas aeruginosa, Bacillus subtilis, and MRSE. All lipopeptides showed high selectivity toward microbial strains as compared to human red blood cells (HC50 > 250 μg/mL). Moreover, most potent lipopeptides (LP16 and LP23) did not induce drug resistance in S. aureus even after 15 rounds of passaging. In addition, a representative lipopeptide (LP16) showed tryptic stability for 24 h. These results suggest the potential of short cationic lipopeptides to boost the discovery of future antimicrobial therapeutics.

Antibacterial evaluation of structurally amphipathic, membrane active small cationic peptidomimetics: Synthesized by incorporating 3-amino benzoic acid as peptidomimetic element

A new series of small cationic peptidomimetics were synthesized by incorporating 3-amino benzoic acid (3-ABA) in a small structural framework with the objective to mimic essential properties of natural antimicrobial peptides (AMPs). The new design approach resulted into improvement of activity and selectivity in comparison to linear peptides and allowed us to better understand the influence of structural amphipathicity on biological activity. Lead peptidomimetics displayed antibacterial activities against resistant pathogens (MRSA & MRSE). A calcein dye leakage experiment revealed a membranolytic effect of 4g and 4l which was further confirmed by fluorescence microscopy. In addition, proteolytic stability and no sign of resistance development against Staphylococcus aureus and MRSA demonstrate their potential for further development as novel antimicrobial therapeutics.

Small cationic antimicrobial peptidomimetics: emerging candidate for the development of potential anti-infective agents.

Rapid increase in the emergence and spread of microbes resistant to conventionally used antibiotics has become a major threat to global health care. Antimicrobial peptides (AMPs) are considered as a potential source of novel antibiotics because of their numerous advantages such as broad-spectrum activity, lower tendency to induce resistance, immunomodulatory response and unique mode of action. However, AMPs have several drawbacks such as; susceptibility to protease degradation, toxicity and high costs of manufacturing. Therefore, extensive research efforts are underway to explore the therapeutic potential of these fascinating natural compounds. This review highlights the potential of small cationic antimicrobial peptidomimetics (SCAMPs; M.W. ≅ 700 Da) as new generation antibiotics. In particular, we focused on recently identified small active pharmacophore from bulky templates of native AMPs, β-peptides, and lipopeptides. In addition, various design strategies recently undertaken to improve the physicochemical properties (proteolytic stability & plasma protein binding) of small cationic peptides have also been discussed.

Convenient synthesis, anticancer evaluation and QSAR studies of some thiazole tethered indenopyrazoles

A convenient one-pot synthesis of twelve new thiazole tethered indeno[1,2-c]pyrazol-4-ones (3a–3l) was carried out by three-component reaction between 1,3-diketones, thiosemicarbazide and α-bromoketones in high yields. Wolff-Kishner reduction of indeno[1,2-c]pyrazol-4-ones (3a–3l) led to the formation of corresponding indeno[1,2-c]pyrazoles (4a–4l) in moderate-to-good yields. The structures of all the synthesized indenopyrazoles were elucidated by IR, 1H NMR, 13C NMR and mass spectral techniques. In vitro cytotoxicity of thiazole tethered indenopyrazoles (3a–3l & 4a–4l) was evaluated against different human cancer cell lines, viz. human renal carcinoma (A498), human colorectal adenocarcinoma (HT29), human breast adenocarcinoma (MCF-7), human hepatocellular carcinoma (HepG2) and normal cell line, i.e., normal rat kidney epithelial (NRK). Among all the tested derivatives, 4a, 4d and 4h exhibited better activity against HT29 cancer cell line. The statistically significant QSAR models were developed for all the cancer cell lines using multiple linear regression analysis to understand the observed activity trend on structural basis.Graphical Abstract

In Vitro and In Vivo Evaluation of Small Cationic Abiotic Lipopeptides as Novel Antifungal Agents

We investigated the antifungal potential of short lipopeptides against clinical fungal isolates with an objective to evaluate their clinical feasibility. All tested lipopeptides exhibit good antifungal activity with negligible difference between the MICs against susceptible and drug‐resistant clinical fungal isolates. The MTT assay results revealed the lower cytotoxicity of lipopeptides toward mammalian cells (NRK‐52E). In particular, LP24 displayed highest potency against most of the tested fungal isolates with MICs in the range of 1.5–4.5 μg/mL. Calcein dye leakage experiments with model membrane suggested the membrane‐active mode of action for LP24. Extending our work from model membranes to intact Aspergillus fumigatus in scanning electron micrographs, we could visualize surface perturbation caused by LP24. LP24 (5 mg/kg) significantly reduces the A. fumigatus burden among the various organs of infected animals, and 70% of the infected mice survived when observed for 28 days. This study underscores the potential of small cationic abiotic lipopeptides to develop into the next‐generation antimicrobial therapy.

Development of novel membrane active lipidated peptidomimetics active against drug resistant clinical isolates

A new series of small cationic lipidated peptidomimetics have been synthesized and found to be highly active against several susceptible as well as drug resistant clinical isolates of bacteria and fungi. All lipidated peptidomimetics do not cause significant lysis of human erythrocytes (HC50>200μg/mL). Calcein dye leakage experiment revealed membranolytic effect of LPEP08 which was further confirmed by scanning electron microscopy (SEM). The involvement of intracellular targets as an alternate mode of action was precluded by DNA retardation assay. Additionally, LPEP08 exhibit high proteolytic stability and dose not elicit resistance against drug resistant clinical isolate of Staphylococcusaureus, even after 16 rounds of passaging. These results demonstrate the potential of lipidated peptidomimetics as biocompatible anti-infective therapeutics.