Tailoring an antibacterial peptide of human lysosomal cathepsin G to enhance its broad-spectrum action against antibiotic-resistant bacterial pathogens

Neutrophils contain several cationic antimicrobial proteins or peptides (CAPs) that exert antibiotic-like action against bacteria. These host-derived antibiotics kill susceptible bacteria by oxygen-independent mechanisms. Considerable interest in their activity has been generated in recent years due not only to their likely important role in innate host defense against infection, but also their possible use as therapeutic agents in treating infections caused by antibiotic-resistant pathogens. We have studied the antibacterial properties of human lysosomal cathepsin G (cat G). This highly cationic serine protease contains at least three antibacterial regions that by themselves can exert antibacterial action against Gram-negative bacteria, such as Pseudomonas aeruginosa. Only one of these peptides, defined by residues 117-136 of full-length cat G, has bactericidal action against Gram-positive pathogens, such as Staphylococcus aureus. Due to the broad-spectrum antibacterial action of this peptide, we have sought to define the amino acids within its primary sequence required for this activity and have developed variants with improved activity. This review emphasizes the importance of both cationicity and hydrophobicity as necessary characteristics for the antibacterial action of CAPs. It also proposes the strategy that naturally occurring large human CAPs can be dissected to smaller CAPs and then modified to enhance their activity in vitro. This approach could prove beneficial to those interested in developing antimicrobial peptides as therapeutic agents.     

Lanthanides as anticancer agents

The application of inorganic chemistry to medicine is a rapidly developing field, and novel therapeutic and diagnostic metals and metal complexes are now having an impact on medical practice. Advances in biocoordination chemistry are crucial for improving the design of compounds to reduce toxic side effects and understand their mechanisms of action. A lot of metal-based drugs are widely used in the treatment of cancer. The clinical success of cisplatin and other platinum complexes is limited by significant side effects acquired or intrinsic resistance. Therefore, much attention has focused on designing new coordination compounds with improved pharmacological properties and a broader range of antitumor activity. Strategies for developing new anticancer agents include the incorporation of carrier groups that can target tumor cells with high specificity. Also of interest is to develop complexes that bind to DNA in a fundamentally different manner than cisplatin, in an attempt to overcome the resistance pathways that have evolved to eliminate the drug. This review focuses on recent advances in developing lanthanide anticancer agents with an emphasis on lanthanide coordination complexes. These complexes may provide a broader spectrum of antitumor activity. They were compared with classical platinum anticancer drugs. Lanthanides are also of interest because of their therapeutic radioisotopes. The dominant pharmacological applications of lanthanides are as agents in radioimmunotherapy and photodynamic therapy.     

1,2,3-Triazole hybrids as anticancer agents: A review

Despite the advancements in the development of anticancer agents, more effective and safer anticancer drugs still need to be developed as the current agents cause unwanted side effects and many patients have become drug resistant. 1,2,3-Triazoles, due to their remarkable biological potential, have received considerable attention in drug discovery for the development of anticancer agents. The present review article presents an overview of the recent advances in 1,2,3-triazole hybrids with anticancer potential over the last 2 years, their chemical structures, structure–activity relationships, and mechanisms of action, as well as insights into the docking studies.     

Anticancer activity of undecapeptide analogues derived from antimicrobial peptide, Brevinin-1EMa

In spite of great advances in cancer therapy, cancer remains the major cause of death throughout the world. The increasing resistance of cancer cells towards current anticancer drugs requires development of anticancer agents with a new mode of action. Some antimicrobial peptides have become therapeutic candidates as new anticancer agents. As part of an effort to develop new antimicrobial and/or anticancer agents from natural peptides with low molecular weights, we have investigated the shortest bioactive analogues, which were derived from a 24-residue antimicrobial peptide, Brevinin-1EMa. Recently, we found four bioactive undecapeptides derived from a cationic, amphipathic α-helical, 11-residue peptide (named herein GA-W2: FLGWLFKWASK-NH(2)) (Won et al., 2011). In order to identify the potential of these peptides as anticancer agents, we investigated the anticancer activity of four undecapeptides against seven tumor cell lines such as A498 (kidney), A549 (lung), HCT116 (colon), MKN45 (stomach), PC-3 (prostate), SK-MEL-2 (skin) and SK-OV-3 (ovary). GA-K4 (FLKWLFKWAKK-NH(2)), which had the most potent antimicrobial activity of the four undecapeptides, also exhibited the most potent anticancer activity and synergistic effect in combination with doxorubicin. Therefore, GA-K4 peptide may be a potentially useful candidate as an anticancer peptide agent.     

Newer treatment options for skin and soft tissue infections

In recent years, serious skin and soft tissue infections (SSTIs) caused by multidrug resistant pathogens have become more common. While the majority of SSTIs are caused by Staphylococcus aureus or beta-haemolytic streptococci that are methicillin/oxacillin susceptible, the emergence of methicillin-resistant and vancomycin-resistant community-acquired and nosocomial Gram-positive pathogens has created a need for different therapeutic agents, such as linezolid, quinupristin/dalfopristin, daptomycin, and newer generation carbapenems and fluoroquinolones. This review focuses on agents presently in clinical development for the treatment of SSTIs caused by Gram-positive pathogens such as staphylococci, streptococci and enterococci including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). Newer-generation carbapenems, such as meropenem and ertapenem, are characterised by a broad-spectrum of activity against Gram-positive and -negative aerobes and anaerobes, and are resistant to hydrolysis by many beta-lactamases. Current-generation fluoroquinolones, such as levofloxacin, moxifloxacin and gatifloxacin, have demonstrated better eradication rates for S. aureus than conventional penicillin and cephalosporins. These antimicrobial agents can be used to treat methicillin-susceptible staphylococcal and streptococcal strains. Oxazolidinones, streptogramin combinations and cyclic lipopeptides have novel mechanisms of action and have been studied in several multinational phase III clinical trials in the treatment of complicated and uncomplicated SSTIs. They possess a broad spectrum of activity against multidrug-resistant pathogens, including MRSA and VRE. Linezolid has been shown to be active against a wide variety of community-acquired and nosocomial antimicrobial-resistant pathogens with comparability to vancomycin, as well as resulting in reduced lengths of hospital stay. Cyclic lipopeptides such as daptomycin have a unique mechanism of action by disruption of bacterial membrane electric potentials with less likelihood for development of cross-resistance. Daptomycin has recently been US FDA approved for the treatment of complicated SSTI. However, rapid development of resistance to some of these newer agents has already been reported and this trend magnifies the importance of further need for effective antimicrobial agents. Several investigational agents, such as dalbavancin, oritavancin and tigecycline, are in advanced stages of development and are likely to proceed to licensing in the next few years. With their long half-lives, these agents have an advantage of less frequent dose administration with more rapid bactericidal activity and less likelihood for development of resistance. However, because of their proven activity against highly resistant organisms, these antibacterial agents should be reserved only for life-threatening situations and/or when resistant pathogens are suspected. Rational antimicrobial use coupled with awareness of infection control measures is paramount to avert the emergence of multidrug-resistant organisms.     

Soy saponins and the anticancer effects of soybeans and soy-based foods

While the cancer protective effect of soy-based diets has been the subject of numerous studies, the constituents of soy that may give rise to this effect remain elusive. Recent publications describing anticancer activity of crude and purified soybean saponins have sparked a renewed interest in these compounds. In this review, I summarize the epidemiological studies concerning the cancer protective effects of soy and the efforts to elucidate the constituents responsible for this effect. The recent reports of the anticancer activity of soy saponins is placed in context with reports of promising anticancer activity of structurally related non-dietary saponins from other legumes. While recent studies have demonstrated a direct effect of soy saponins on cancer cells, alternative mechanisms of cancer prevention by these agents are also discussed. It is concluded that the soy saponins may represent promising leads both in terms of elucidating the soy constituents involved in the cancer protective effect of soy as well as in the discovery of anticancer agents with novel mechanisms of action.     

HAZ,a novel peptide with broad-spectrum antibacterial activity

ObjectiveThe growing microbial resistance to antibiotics is a global public concern, which creates serious needs for newer antimicrobial agents. Antimicrobial peptides (AMPs) are increasingly exploited in drug development as therapeutic candidates. Here, we aimed to design and characterize a novel peptide with broad spectrum antimicrobial activity.MethodsHybridization and sequence modification approaches were used to design the novel peptide, named HAZ, aiming at optimizing the physicochemical parameters involved in antimicrobial activity. Peptide activities were assessed alone or combined with different selected antibiotics against various sensitive and drug-resistant bacterial strains. In addition, the hemolysis and the cytotoxic activities of HAZ peptide were evaluated on human red blood cells and epithelial adenocarcinoma cells (A549), respectively.ResultsHAZ peptide was sequentially modified to result in favored physicochemical parameters (helicity 95.24 %, hydrophobic ratio 47 %, and net charge of 8 + ). Functional assessment of HAZ revealed significant antimicrobial activity, with MIC values of 15 – 20 µM against tested bacterial strains. It also exhibited biofilm eradication activity at slightly higher concentrations. HAZ-antibiotics combinations exhibited a synergistic action mode that led to dramatic decrease in the MIC values for both HAZ peptide and the antibiotic. Such efficacy was accompanied with minimal hemolytic toxicity on human erythrocytes. Importantly, HAZ displayed promising anticancer activity against human lung cancer cells.ConclusionRationally-designed antimicrobial peptides offer promising alternatives to the current antibiotics for management of infectious diseases. HAZ peptide is a broad-spectrum AMP, and a promising candidate for antimicrobial and anticancer drug development.     

Isatin–azole hybrids and their anticancer activities

Isatin and azole moieties, which have the ability to form various noncovalent interactions with different therapeutic targets, are common pharmacophores in drug development. Isatin and azole derivatives possess promising in vitro and in vivo anticancer activity, and many of them, such as semaxanib, sunitinib, and carboxyamidotriazole, could be used to treat various cancers. Thus, it is conceivable that hybridization of the isatin moiety with azole may provide a valuable therapeutic intervention for the treatment of cancer. Substantial efforts have been made to develop isatin–azole hybrids as novel anticancer agents, and some of the isatin–azole hybrids exhibited considerable activity. This review emphasizes isatin–azole hybrids with potential anticancer activity, covering articles published between 2010 and 2019. The structure–activity relationships as well as the mechanisms of action are also discussed to provide insights for the rational design of more effective candidates.     

Artemisinin-derived dimers as potential anticancer agents: Current developments,action mechanisms,and structure–activity relationships

Anticancer agents play a pivotal role in cancer treatment. However, most of the anticancer drugs currently used in the clinics have a severe anticancer scenario, as well as low specificity and fatal side effects. Thus, there is an urgent demand to develop novel drugs with great efficacy, high specificity, and low side effects. Artemisinin and its semisynthetic derivatives are mainstays of chemotherapy against malaria, and artemisinin-based compounds, especially artemisinin-derived dimers, also exhibit excellent in vitro and in vivo anticancer activity. The structure–activity relationship (SAR) demonstrated that the linker between the two artemisinin moieties influenced the anticancer activity significantly; so, the rational design of the linker may provide valuable therapeutic intervention for the treatment of cancer. This review outlines the potential anticancer activity of artemisinin-derived dimers tethered by different linkers. The SARs, as well as mechanisms of action, are discussed to provide insights for the rational design of more effective dimers.     

Cellular redox pathways as a therapeutic target in the treatment of cancer

The vulnerability of some cancer cells to oxidative signals is a therapeutic target for the rational design of new anticancer agents. In addition to their well characterized effects on cell division, many cytotoxic anticancer agents can induce oxidative stress by modulating levels of reactive oxygen species (ROS) such as the superoxide anion radical, hydrogen peroxide and hydroxyl radicals. Tumour cells are particularly sensitive to oxidative stress as they typically have persistently higher levels of ROS than normal cells due to the dysregulation of redox balance that develops in cancer cells in response to increased intracellular production of ROS or depletion of antioxidant proteins. In addition, excess ROS levels potentially contribute to oncogenesis by the mediation of oxidative DNA damage. There are several anticancer agents in development that target cellular redox regulation. The overall cellular redox state is regulated by three systems that modulate cellular redox status by counteracting free radicals and ROS, or by reversing the formation of disulfides; two of these are dependent on glutathione and the third on thioredoxin. Drugs targeting S-glutathionylation have direct anticancer effects via cell signalling pathways and inhibition of DNA repair, and have an impact on a wide range of signalling pathways. Of these agents, NOV-002 and canfosfamide have been assessed in phase III trials, while a number of others are undergoing evaluation in early phase clinical trials. Alternatively, agents including PX-12, dimesna and motexafin gadolinium are being developed to target thioredoxin, which is overexpressed in many human tumours, and this overexpression is associated with aggressive tumour growth and poorer clinical outcomes. Finally, arsenic derivatives have demonstrated antitumour activity including antiproliferative and apoptogenic effects on cancer cells by pro-oxidant mechanisms, and the induction of high levels of oxidative stress and apoptosis by an as yet undefined mechanism. In this article we review anticancer drugs currently in development that target cellular redox activity to treat cancer.     

Recent advances in isatin hybrids as potential anticancer agents

The isatin framework is a useful template for the development of novel anticancer agents. This is exemplified by the fact that several isatin-based anticancer agents, such as semaxanib, sunitinib, nintedanib, and hesperadin, are already in use or under clinical trials for the treatment of diverse kinds of cancers. Isatin-based hybrids could be obtained by incorporating other anticancer pharmacophores into the isatin skeleton and they have the potential to overcome drug resistance with reduced side effects. Thus, isatin-based hybrids may provide attractive scaffolds for the development of novel anticancer agents. This review covers the recent advances of isatin-based hybrids with anticancer activity, covering articles published between 2001 and 2019. The anticancer activities of these molecules and the structure–activity relationships are also discussed. The purpose of this review article is to set up the direction for the design and development of isatin-based hybrids with high efficacy and low toxicity.     

The antiproliferative and immunotoxic effects of L-canavanine and L-canaline

L-Canavanine and its arginase-catalyzed metabolite, L-canaline, are two novel anticancer agents in development. Since the immunotoxic evaluation of agents in development is a critical component of the drug development process, the antiproliferative effects of L-canavanine and L-canaline were evaluated in vitro. Both L-canavanine and L-canaline were cytotoxic to peripheral blood mononucleocytes (PBMCs) in culture. Additionally, the mononucleocytes were concurrently exposed to either L-canavanine or L-canaline and each one of a series of compounds that may act as metabolic inhibitors of the action of L-canavanine and L-canaline (L-arginine, L-ornithine, D-arginine, L-lysine, L-homoarginine, putrescine, L-omega-nitro arginine methyl ester and L-citrulline). The capacity of these compounds to overcome the cytotoxic effects of L-canavanine or L-canaline was assessed in order to provide insight into the biochemical mechanisms that may underlie the toxicity of these two novel anticancer agents. The results of these studies suggest that the mechanism of L-canavanine toxicity is mediated through L-arginine-utilizing mechanisms and that the L-canavanine metabolite, L-canaline, is toxic to human PBMCs by disrupting polyamine biosynthesis. The elucidation of the biochemical mechanisms associated with the effects of L-canavanine and L-canaline on lymphoproliferation may be useful for maximizing the therapeutic effectiveness and minimizing the toxicity of these novel anticancer agents.     

Telomeres as targets for anticancer therapies

INTRODUCTION: The limitless replicative potential of cancer cells relies on telomere integrity (which is guaranteed by a complex interaction between several specialized proteins and telomeric DNA) and the activation of specific mechanisms for telomere length maintenance. Two mechanisms are currently known in human cancer, namely telomerase activity and the alternative lengthening of telomere pathway. EXPERT OPINION: In this review, we summarize the available data concerning the therapeutic strategies proposed thus far and the current challenges posed for the development of innovative telomere-based therapeutic approaches with broad-spectrum anticancer activity and for their translation into the clinical setting. AREAS COVERED: Due to their essential role in tumor cell proliferation, telomere maintenance mechanisms have become extremely attractive targets for the development of new anticancer interventions. Although numerous efforts have been made to identify specific approaches to interfere with telomere maintenance mechanisms in human cancers, the only molecule currently tested in clinical trials is the oligonucleotide GRN163L. However, a growing body of evidence suggests that interfering with telomeres, through the direct targeting of telomeric G-quadruplex structures, may be a valuable antitumor therapeutic strategy, independent of the specific telomere maintenance mechanism operating in the tumor.     

The prodigiosins, proapoptotic drugs with anticancer properties

The family of natural red pigments, called prodigiosins (PGs), characterised by a common pyrrolylpyrromethene skeleton, are produced by various bacteria. Some members have immunosuppressive properties and apoptotic effects in vitro and they have also displayed antitumour activity in vivo. Understanding the mechanism of action of PGs is essential for drug development and will require the identification and characterisation of their still unidentified cell target. Four possible mechanisms of action have been suggested for these molecules: (i) PGs as pH modulators; (ii) PGs as cell cycle inhibitors; (iii) PGs as DNA cleavage agents; (iv) PGs as mitogen-activated protein kinase regulators. Here, we review the pharmacological activity of PG and related compounds, including novel synthetic PG derivatives with lower toxicity and discuss the mechanisms of action and the molecular targets of those molecules. The results reported in this review suggest that PGs are a new class of anticancer drugs, which hold out considerable promise for the Pharmacological Industry.     

New agents in development for the treatment of bacterial infections

New antibacterial agents to treat infections caused by antibiotic-susceptible and antibiotic-resistant pathogens are in various stages of clinical development. In this review are compounds with demonstrated activity against methicillin-resistant staphylococci including investigational cephalosporins, carbapenems, and a new tetracycline, as well as glycopeptides effective against vancomycin-resistant enterococci (VRE), and fluoroquinolones with improved potency against respiratory pathogens and multidrug-resistant Gram-positive bacteria. Although most recent progress has occurred in the identification of agents for Gram-positive infections, broad-spectrum carbapenems are described for the treatment of multidrug-resistant Gram-negative pathogens. Also discussed are agents with mechanisms of action other than inhibition of protein synthesis, penicillin-binding proteins, and DNA topoisomerases; among these are inhibitors of bacterial fatty acid biosynthesis, peptidoglycan synthesis, and dihydrofolate reductase.     

Drug therapy reviews: nitrofurantoin.

Mechanism of action, antimicrobial spectrum, pharmacology, adverse reactions and therapeutic uses of nitrofurantoin, a broad-spectrum antimicrobial agent, are discussed. The frequency and potential severity of reactions attributed to nitrofurantoin, plus its inability to achieve therapeutic blood concentrations, relegate this drug to a position of secondary importance. Nitrofurantoin compares favorably with other standard agents for the therapy of acute and recurrent urinary tract infections in women which may be caused by susceptible organisms, and it is an effective chemoprophylactic agent for patients with recurrent urinary tract infections. The compound has no apparent adverse effects on the developing fetus and can be used in pregnant women. This is not sanctioned by the package insert, however. Nitrofurantoin should not be administered when the possibility of bacteremia exists, as the drug does not achieve therapeutic serum levels when administered orally. Nitrofurantoin is contraindicated for patients with renal insufficiency. The value of this compound for men with acute urinary tract infection, recurrent urinary tract infection, acute bacterial prostatitis or chronic bacterial prostatitis has not been established. There are no indications for prescribing parenteral nitrofurantoin.     

Bacterial efflux pump inhibition

Drug efflux is recognized as a clinically relevant mechanism of antimicrobial drug resistance in selected species of bacteria. Membrane-based polypeptides belong to distinct protein superfamilies, the members of which are related by structural characteristics, mechanism of action and energy source for the transport process. These membrane-based polypeptides mediate drug efflux, and some of these proteins, the multidrug efflux proteins, are capable of extruding numerous structurally dissimilar antimicrobial agents and biocides. Inhibition of these pumps can decrease intrinsic resistance, reverse acquired resistance and reduce the emergence of mutants with higher-level target-based mutational resistance. In vitro and limited in vivo investigations have shown that combining efflux pump inhibitors with antimicrobial agents that are pump substrates can result in the recovery of clinically relevant activity of those compounds. The identification of broad-spectrum efflux pump inhibitors may reduce the need, and thus cost, of discovery and development of new antimicrobial agents that are not pump substrates.     

Antimicrobial drug delivery in food animals and microbial food safety concerns: an overview of in vitro and in vivo factors potentially affecting the animal gut microflora

This review provides an overview of considerations particular to the delivery of antimicrobial agents to food animals. Antimicrobial drugs are used in food animals for a variety of purposes. These drugs may have therapeutic effects against disease agents, or may cause changes in the structure and/or function of systems within the target animal. Routes of administration, quantity, duration, and potency of an antimicrobial drug are all important factors affecting their action(s) and success. Not only might targeted pathogens be affected, but also bacteria residing in (or on) the treated food animals, especially in the intestines (gastrointestinal tract microflora). Resistance to antimicrobial agents can occur through a number of mechanisms. The extent to which resistance develops is greatly affected by the amount of drug [or its metabolite(s)] a bacterium is exposed to, the duration of exposure, and the interaction between an individual antimicrobial agent and a particular bacterium. The impact of antimicrobial agents on the emergence of resistance in vitro and in vivo may not readily correlate.