Identification and design of antimicrobial peptides for therapeutic applications

Indiscriminate use of antibiotics has led to a rapid increase of antibiotic resistance among microbes which has increased the need to develop novel antimicrobial agents to fight various infectious diseases. Peptide antibiotics signify a novel class of therapeutic agents and have been isolated from a wide variety of multi-cellular organisms. Peptide antibiotics have shown broad-spectrum antimicrobial activity and they not only kill different bacteria, but also kill various fungi, parasites, protozoans and cancerous cells. Peptides bear several properties that make them particularly attractive such as their small size, rapid activity and a low chance for development of resistance. Because of these distinct properties, the focus for research on antimicrobial peptides has increased tremendously in the recent years. Despite their potential, only selected cationic antimicrobial peptides have been able to enter in clinical trials. Therefore, there is a pressing need to develop new approaches to identify novel antimicrobial peptide therapeutics replacing conventional antibiotics. Recent findings strongly suggest that one can design a new generation of antimicrobials peptides with a wide range of systemic and topical applications against bacterial infections. In this review, we focus on the identification and design of novel antimicrobial peptides for therapeutic applications based on different approaches and strategies. This review also highlights some recent advances in the study of the molecular basis of anti-microbial activity in these peptides, their current pharmacological and clinical development and future directions and applications.     

Discovery of ferrocene-carborane derivatives as novel chemical antimicrobial agents against multidrug-resistant bacteria

Antimicrobial resistance has now become a very serious global public health problem. New drug discovery and development are urgently needed to combat the growing threat of multidrug-resistant (MDR) bacteria. The aim of this study was to explore the potential application of three ferrocene-carborane derivatives as new promising agents to confront the problem of increasing antibiotic resistance. The results of agar diffusion bioassay, minimal inhibitory concentrations (MIC) testing and time-kill assay illustrate their broad-spectrum antimicrobial activities to both American Type Culture Collection (ATCC) control strains and MDR clinical isolates. It is evident that the relevant antimicrobial properties are all in a dose-dependent manner and gradually transform into a bactericidal effect from a bacteriostatic effect with the increasing of the drug concentration. Furthermore, these ferrocene-carborane derivatives have no/little toxic effect on normal cells like HELF cells and lead to little hemolysis at their MICs. This raises the possibility to develop novel antimicrobial drugs using these new ferrocene carborane derivants.     

Bio-Organometallic Derivatives of Antibacterial Drugs

Overuse and misuse of antibacterial drugs has resulted in bacteria resistance and in an increase in mortality rates due to bacterial infections. Therefore, there is an imperative necessity of new antibacterial drugs. Bio-organometallic derivatives of antibacterial agents offer an opportunity to discover new active antibacterial drugs. These compounds are well-characterized products and, in several examples, their antibacterial activities have been studied. Both inhibition of the antibacterial activity and strong increase in the antibiotic activity of the parent drug have been found. The synthesis of the main classes of bio-organometallic derivatives of these drugs, as well as examples of the use of structure–activity relation (SAR) studies to increase the activity and to understand the mode of action of bio-organometallic antimicrobial peptides (BOAMPs) and platensimicyn bio-organometallic mimics is presented in this article.     

Polysaccharide Chemistry in Drug Delivery,Endocrinology, and Vaccines

Polysaccharides, due to their outstanding properties, have attracted the attention of researchers, working in the biomedical field and especially of those working in drug delivery. Modified/functionalized polysaccharides further increase the importance for various applications. Delivery of therapeutics for diverse ailments in different endocrine glands and hormones safely, is a focal point of researchers working in the field. Among the routes followed, the transdermal route is preferred due to non-exposure of active moieties to the harsh gastric environment and first-pass metabolism. This review starts with the overview of polysaccharides used for the delivery of various therapeutic agents. Advantages of polysaccharides used in the transdermal route are addressed in detail. Types of polysaccharides will be elaborated through examples, and in this context, special emphasis will be on the polysaccharides being used for synthesis of the membranes/films. Techniques employed for their modification to design novel carriers for therapeutics delivery will also be discussed. The review will end with a brief discussion on recent developments and future perspectives for delivery of therapeutic agents, and vaccine development.     

Antimicrobial Properties of Chitosan and Chitosan Derivatives in the Treatment of Enteric Infections

Antibiotics played an important role in controlling the development of enteric infection. However, the emergence of antibiotic resistance and gut dysbiosis led to a growing interest in the use of natural antimicrobial agents as alternatives for therapy and disinfection. Chitosan is a nontoxic natural antimicrobial polymer and is approved by GRAS (Generally Recognized as Safe by the United States Food and Drug Administration). Chitosan and chitosan derivatives can kill microbes by neutralizing negative charges on the microbial surface. Besides, chemical modifications give chitosan derivatives better water solubility and antimicrobial property. This review gives an overview of the preparation of chitosan, its derivatives, and the conjugates with other polymers and nanoparticles with better antimicrobial properties, explains the direct and indirect mechanisms of action of chitosan, and summarizes current treatment for enteric infections as well as the role of chitosan and chitosan derivatives in the antimicrobial agents in enteric infections. Finally, we suggested future directions for further research to improve the treatment of enteric infections and to develop more useful chitosan derivatives and conjugates.     

Comprehensive review in moisture retention mechanism of polysaccharides from algae,plants, bacteria and fungus

Polysaccharides have attracted much attention due to their significant bio-activities. This review aims to summarize the main polysaccharides sources of related polysaccharides from algae, plants, fungus, and bacteria, and give insights into the structure–activity relationship between the moisture retention and structural characteristics of polysaccharides. The molecular weight, functional groups, polysaccharide modifications and apparent structure of polysaccharides are closely related to the moisturizing properties of polysaccharides in terms of moisturizing conformation. Based on recent moisturizing pieces of evidence, we propose a new framework focusing on the moisturizing intrinsic and extrinsic mechanisms. Polysaccharides molecular weight has different effects on moisturizing property. The extrinsic moisturization is mainly via the formation of hydrogen bonds between polysaccharides, the intrinsic moisturizing is mainly by regulating the production of some tight junction proteins. Accordingly, this review could further open the door for the production and application of polysaccharides as novel moisturizing agents in the cosmetic field.     

Seaweed Polysaccharide Based Products and Materials: An Assessment on Their Production from a Sustainability Point of View

Among the various natural polymers, polysaccharides are one of the oldest biopolymers present on the Earth. They play a very crucial role in the survival of both animals and plants. Due to the presence of hydroxyl functional groups in most of the polysaccharides, it is easy to prepare their chemical derivatives. Several polysaccharide derivatives are widely used in a number of industrial applications. The polysaccharides such as cellulose, starch, chitosan, etc., have several applications but due to some distinguished characteristic properties, seaweed polysaccharides are preferred in a number of applications. This review covers published literature on the seaweed polysaccharides, their origin, and extraction from seaweeds, application, and chemical modification. Derivatization of the polysaccharides to impart new functionalities by chemical modification such as esterification, amidation, amination, C-N bond formation, sulphation, acetylation, phosphorylation, and graft copolymerization is discussed. The suitability of extraction of seaweed polysaccharides such as agar, carrageenan, and alginate using ionic solvent systems from a sustainability point of view and future prospects for efficient extraction and functionalization of seaweed polysaccharides is also included in this review article.     

New strategy for reversing biofilm-associated antibiotic resistance through ferrocene-substituted carborane ruthenium(II)-arene complex

Bacterial biofilms are inherently resistant to antimicrobial agents and are difficult to eradicate with conventional antimicrobial agents, resulting in many persistent and chronic bacterial infections. In this contribution, a new strategy for reversing the biofilm-associated antibiotic resistance has been explored by induction of a carborane ruthenium(II)-arene complex (FcRuSB). Our results demonstrate that the FcRuSB could be utilized as an inducer to efficiently reverse the biofilm-associated antibiotic resistance of multidrug-resistant (MDR) clinical isolates of Staphylococcus aureus and Pseudomonas aeruginosa. The induced effect of FcRuSB is correlated with a considerable decrease in the expression of extracellular matrix proteins (EMP) of the two strains. The considerable decrease of the EMP of induced cells, resulting in the reduction of adherence and biofilm formation ability of the two types of MDR pathogens, and then can cause significantly enhanced sensitivity of them to antibiotics.     

Polysaccharides derived from natural sources applied to the development of chemically modified electrodes for environmental applications: A review

Potentially toxic organic and inorganic compounds have been released into the environment by different sources. Due to this detrimental problem, the modern analytical chemistry has increasingly acted in the interface of knowledge in terms of developing methods which are robust, efficient, sensitive, inexpensive, and aim at meeting green chemistry principles. From an electroanalytical standpoint, the application of polysaccharides derived from natural sources in the development of chemically modified electrodes has increased in the last decades. Chitosan, cellulose and other polysaccharides have been widely used in the development of modified electrodes due to their high mechanical strength, relatively low cost, and green features. Several studies have reported in the past few years that chemically modified electrodes elaborated with these polysaccharides usually present superior analytical properties as compared to the conventional electrodes. This review describes the general aspects of these polysaccharides, extraction sources, characterization methods, derivatives and crosslinking processes as well as a comprehensive overview of their several applications in the development of new sensors applied to environmental samples.     

Molecular Assembly of Polysaccharide‐Based Microcapsules and Their Biomedical Applications

Advanced multifunctional microcapsules have revealed great potential in biomedical applications owing to their tunable size, shape, surface properties, and stimuli responsiveness. Polysaccharides are one of the most acceptable biomaterials for biomedical applications because of their outstanding virtues such as biocompatibility, biodegradability, and low toxicity. Many efforts have been devoted to investigating novel molecular design and efficient building blocks for polysaccharide‐based microcapsules. In this Personal Account, we first summarize the common features of polysaccharides and the main principles of the design and fabrication of polysaccharide‐based microcapsules, and further discuss their applications in biomedical areas and perspectives for future research.     

Catalytic Reductive N‐Alkylations Using CO2 and Carboxylic Acid Derivatives: Recent Progress and Developments

N‐Alkylamines are key intermediates in the synthesis of fine chemicals, dyes, and natural products, and hence are highly valuable building blocks in organic chemistry. Consequently, the development of greener and more efficient procedures for their production continues to attract the interest of both academic and industrial chemists. Reductive procedures such as reductive amination or N‐alkylation through hydrogen autotransfer by employing carbonyl compounds or alcohols as alkylating agents have prevailed for the synthesis of amines. In the last few years, carboxylic/carbonic acid derivatives and CO₂ have been introduced as alternative and convenient alkylating sources. The safety, easy accessibility, and high stability of these reagents makes the development of new reductive transformations with them as N‐alkylating agents a useful alternative to existing procedures. In this Review, we summarize reported examples of one‐pot reductive N‐alkylation methods that use carboxylic/carbonic acid derivatives or CO₂ as alkylating agents.     

Review: Antibacterial behavior of carboxylate silver(I) complexes

Since ancient times, silver ions have been known to be effective against a broad range of micro-organisms but in the last decade, this metal has been greatly studied because of their antimicrobial capability against a wide range of bacteria, viruses, and fungi. For the same reason, it is the most extensively studied metal with antibacterial applications in medicine. Besides applications, the antimicrobial activity is associated with high effectiveness, low toxicity, and virtually no resistance of micro-organisms to the presence of this metal. The appearance of new bacterial strains resistant to antibiotics is a serious health problem; so, there is a strong incentive to develop new bactericides. This makes current research in bactericidal silver complexes particularly important. This review summarizes the most important aspect related to coordination chemistry of Ag(I) carboxylate complexes and their influence as antibacterial agents.     

Antimicrobial and Wound Treatment Aspects of Micro‐ and Nanoformulations of Carboxymethyl,Dialdehyde, and TEMPO‐Oxidized Derivatives of Cellulose: Recent Advances

The remedy for infected chronic wounds such as diabetic foot ulcers is more complicated particularly in the case of patients with an inefficient immune system. Also, fighting against microbial infections in the wound site by available antibiotics may not be effective because of emerging antibiotic resistance properties among pathogenic bacteria and fungi. Recently, applications of micro‐ and nanoformulations of biomaterials have demonstrated improved therapeutic abilities for wound dressings. In this way, carboxymethyl, dialdehyde, and 2,2,6,6‐tetramethylpiperidine‐1‐oxyl‐oxidized celluloses are common biomaterials having outstanding physicochemical and therapeutic properties compared to unmodified cellulose. Therefore, in this review, recent progress in the field of wound healing and antimicrobial activities of these derivatives are presented and discussed.     

An update on bioactive plant lignans

Lignans are a class of secondary plant metabolites produced by oxidative dimerization of two phenylpropanoid units. Although their molecular backbone consists only of two phenylpropane (C6-C3) units, lignans show an enormous structural diversity. There is a growing interest in lignans and their synthetic derivatives due to applications in cancer chemotherapy and various other pharmacological effects. This review deals with lignans possessing anticancer, antioxidant, antimicrobial, anti-inflammatory and immunosuppressive activities, and comprises the data reported in more than 100 peer-reviewed articles, so as to highlight the recently reported bioactive lignans that could be a first step towards the development of potential new therapeutic agents.     

New Antibiotics for Multidrug-Resistant Bacterial Strains: Latest Research Developments and Future Perspectives

The present work aims to examine the worrying problem of antibiotic resistance and the emergence of multidrug-resistant bacterial strains, which have now become really common in hospitals and risk hindering the global control of infectious diseases. After a careful examination of these phenomena and multiple mechanisms that make certain bacteria resistant to specific antibiotics that were originally effective in the treatment of infections caused by the same pathogens, possible strategies to stem antibiotic resistance are analyzed. This paper, therefore, focuses on the most promising new chemical compounds in the current pipeline active against multidrug-resistant organisms that are innovative compared to traditional antibiotics: Firstly, the main antibacterial agents in clinical development (Phase III) from 2017 to 2020 are listed (with special attention on the treatment of infections caused by the pathogens Neisseria gonorrhoeae, including multidrug-resistant isolates, and Clostridium difficile), and then the paper moves on to the new agents of pharmacological interest that have been approved during the same period. They include tetracycline derivatives (eravacycline), fourth generation fluoroquinolones (delafloxacin), new combinations between one β-lactam and one β-lactamase inhibitor (meropenem and vaborbactam), siderophore cephalosporins (cefiderocol), new aminoglycosides (plazomicin), and agents in development for treating drug-resistant TB (pretomanid). It concludes with the advantages that can result from the use of these compounds, also mentioning other approaches, still poorly developed, for combating antibiotic resistance: Nanoparticles delivery systems for antibiotics.     

Polysaccharide- and β-Cyclodextrin-Based Chiral Selectors for Enantiomer Resolution: Recent Developments and Applications

Polysaccharides, oligosaccharides, and their derivatives, particularly of amylose, cellulose, chitosan, and β-cyclodextrin, are well-known chiral selectors (CSs) of chiral stationary phases (CSPs) in chromatography, because they can separate a wide range of enantiomers. Typically, such CSPs are prepared by physically coating, or chemically immobilizing the polysaccharide and β-cyclodextrin derivatives onto inert silica gel carriers as chromatographic support. Over the past few years, new chiral selectors have been introduced, and progressive methods to prepare CSPs have been exploited. Also, chiral recognition mechanisms, which play a crucial role in the investigation of chiral separations, have been better elucidated. Further insights into the broad functional performance of commercially available chiral column materials and/or the respective newly developed chiral phase materials on enantiomeric separation (ES) have been gained. This review summarizes the recent developments in CSs, CSP preparation, chiral recognition mechanisms, and enantiomeric separation methods, based on polysaccharides and β-cyclodextrins as CSs, with a focus on the years 2019–2020 of this rapidly developing field.     

Synthesis of various fused heterocyclic rings from thiazolopyridine and their pharmacological and antimicrobial evaluations

Various fused-heterocyclic-derivatives containing thiazolopyridine moieties has been synthesized by allowing 5-aminothiazolo[3,2-a]pyridine derivative 1 to undergo annulations reactions with different reagents under different-reaction conditions. The biological assessment of compounds 2 , 11 , 14 , 15 , and 19 showed remarkable antimicrobial activities. In addition, selected derivatives of the products were screened for their anticancer activities against two tumor cell lines using MTT assay and the results showed that some of these compounds have potent cytotoxic effect, as concluded from their IC₅₀ values. Meanwhile, compounds 3a , 7 have exhibited very strong potency as anticancer candidates. Thiazolopyridine structures have been confirmed as a useful lead compounds for the development of new anticancer agents. Molecular docking showed that,-some of the synthesized compounds more suitable inhibitor against-ALR2 with farther alteration in future.     

Integrated Antimicrobial and Nonfouling Zwitterionic Polymers

Zwitterionic polymers are generally viewed as a new class of nonfouling materials. Unlike their poly(ethylene glycol) (PEG) counterparts, zwitterionic polymers have a broader chemical diversity and greater freedom for molecular design. In this Minireview, we highlight recent microbiological applications of zwitterionic polymers and their derivatives, with an emphasis on several unique molecular strategies to integrate antimicrobial and nonfouling properties. We will also discuss our insights into the bacterial nonfouling performance of zwitterionic polymers and one example of engineering zwitterionic polymer derivatives for antimicrobial wound‐dressing applications.     

Synthesis and investigation of binding interactions of 1,4-benzoxazine derivatives on topoisomerase IV in Acinetobacter baumannii$

Abstract

Acinetobacter baumannii has emerged as an important pathogen for nosocomial infections having high morbidity and mortality. This pathogen is notorious for antimicrobial resistance to many common antimicrobial agents including fluoroquinolones, which have both intrinsic and acquired resistance mechanisms. Fluoroquinolones targeting the bacterial topoisomerase II (DNA gyrase and Topo IV) show potent broad-spectrum antibacterial activity by the stabilization of the covalent enzyme–DNA complex. However, their efficacy is now being threatened by an increasing prevalence of resistance. Fluoroquinolones cause stepwise mutations in DNA gyrase and Topo IV, having alterations of their binding sites. Furthermore, the water–Mg⁺² bridge, which provides enzyme–fluoroquinolone interactions, has a significant role in resistance. In this study, 13 compounds were synthesized as 1,4-benzoxazine derivatives which act as bacterial topoisomerase II inhibitors and their antibacterial activities were determined against multi-drug resistant Acinetobacter strains which have ciprofloxacin (CIP) resistant and GyrA mutation. Afterwards we performed docking studies with Topo IV (pdb:2XKK) of these compounds to comprehend their binding properties in Discovery Studio 3.5. The results of this study show significant conclusions to elucidate the resistance mechanism and lead to the design of new antibacterial agents as bacterial topoisomerase II inhibitors.