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Fulltext Cladosporium cladosporioides from the perspectives of medical and biotechnological approaches

AlMatar M, Makky EA

3 Biotech, 2016 Jun;6(1):4.
PMID: 28330073 DOI: 10.1007/s13205-015-0323-4

Fungi are important natural product sources that have enormous potential for the production of novel compounds for use in pharmacology, agricultural applications and industry. Compared with other natural sources such as plants, fungi are highly diverse but understudied. However, research on Cladosporium cladosporioides revealed the existence of bioactive products such as p-methylbenzoic acid, ergosterol peroxide (EP) and calphostin C as well as enzymes including pectin methylesterase (PME), polygalacturonase (PG) and chlorpyrifos hydrolase. p-Methylbenzoic acid has ability to synthesise 1,5-benzodiazepine and its derivatives, polyethylene terephthalate and eicosapentaenoic acid. EP has anticancer, antiangiogenic, antibacterial, anti-oxidative and immunosuppressive properties. Calphostin C inhibits protein kinase C (PKC) by inactivating both PKC-epsilon and PKC-alpha. In addition, calphostin C stimulates apoptosis in WEHI-231 cells and vascular smooth muscle cells. Based on the stimulation of endoplasmic reticulum stress in some types of cancer, calphostin C has also been evaluated as a potential photodynamic therapeutic agent. Methylesterase (PME) and PG have garnered attention because of their usage in the food processing industry and significant physiological function in plants. Chlorpyrifos, a human, animal and plant toxin, can be degraded and eliminated by chlorpyrifos hydrolase.
An Overview of the Activities of Cefiderocol Against Sensitive and Multidrug- Resistant (MDR) Bacteria

AlMatar M, Albarri O, Makky EA, Var I, Köksal F

Mini Rev Med Chem, 2020;20(18):1908-1916.
PMID: 32811410 DOI: 10.2174/1389557520666200818211405

The need for new therapeutics and drug delivery systems has become necessary owing to the public health concern associated with the emergence of multidrug-resistant microorganisms. Among the newly discovered therapeutic agents is cefiderocol, which was discovered by Shionogi Company, Japan as an injectable siderophore cephalosporin. Just like the other β-lactam antibiotics, cefiderocol exhibits antibacterial activity via cell wall synthesis inhibition, especially in Gram negative bacteria (GNB); it binds to the penicillin-binding proteins, but its unique attribute is that it crosses the periplasmic space of bacteria owing to its siderophore-like attribute; it also resists the activity of β-lactamases. Among all the synthesized compounds with the modified C-7 side chain, cefiderocol (3) presented the best and well-balanced activity against multi-drug resistant (MDR) Gram negative bacteria, including those that are resistant to carbapenem. İn this article, an overview of the recent studies on cefiderocol was presented.
A Glance on the Role of Bacterial Siderophore from the Perspectives of Medical and Biotechnological Approaches

AlMatar M, Albarri O, Makky EA, Var I, Köksal F

Curr Drug Targets, 2020;21(13):1326-1343.
PMID: 32564749 DOI: 10.2174/1389450121666200621193018

Iron, which is described as the most basic component found in nature, is hard to be assimilated by microorganisms. It has become increasingly complicated to obtain iron from nature as iron (II) in the presence of oxygen oxidized to press (III) oxide and hydroxide, becoming unsolvable at neutral pH. Microorganisms appeared to produce organic molecules known as siderophores in order to overcome this condition. Siderophore's essential function is to connect with iron (II) and make it dissolvable and enable cell absorption. These siderophores, apart from iron particles, have the ability to chelate various other metal particles that have collocated away to focus the use of siderophores on wound care items. There is a severe clash between the host and the bacterial pathogens during infection. By producing siderophores, small ferric iron-binding molecules, microorganisms obtain iron. In response, host immune cells produce lipocalin 2 to prevent bacterial reuptake of siderophores loaded with iron. Some bacteria are thought to produce lipocalin 2-resistant siderophores to counter this risk. The aim of this article is to discuss the recently described roles and applications of bacterial siderophore.
Novel compounds targeting InhA for TB therapy

AlMatar M, Makky EA, Var I, Kayar B, Köksal F

Pharmacol Rep, 2018 Apr;70(2):217-226.
PMID: 29475004 DOI: 10.1016/j.pharep.2017.09.001

Tuberculosis (TB) is described as lethal disease in the world. Resistant to TB drugs is the main reason to have unfavourable outcomes in the treatment of TB. Therefore, new agents to replace existing drugs are urgently needed. Previous reports suggested that InhA inhibitors, an enoyl-ACP-reductase, might provide auspicious candidates which can be developed into novel antitubercular agents. In this review, we explain the role of InhA in the resistance of isoniazid. Furthermore, five classes of InhA inhibitors, which display novel binding modes and deliver evidence of their prosperous target engagement, have been debated.
Efflux pump inhibitors: new updates

AlMatar M, Albarri O, Makky EA, Köksal F

Pharmacol Rep, 2021 Feb;73(1):1-16.
PMID: 32946075 DOI: 10.1007/s43440-020-00160-9

The discovery of antibiotics ought to have ended the issue of bacterial infections, but this was not the case as it has led to the evolution of various mechanisms of bacterial resistance against various antibiotics. The efflux pump remains one of the mechanisms through which organisms develop resistance against antibiotics; this is because organisms can extrude most of the clinically relevant antibiotics from the interior cell environment to the exterior environment via the efflux pumps. Efflux pumps are thought to contribute significantly to biofilm formation as highlighted by various studies. Therefore, the inhibition of these efflux pumps can be a potential way of improving the activity of antibiotics, particularly now that the discovery of novel antibiotics is becoming tedious. Efflux pump inhibitors (EPIs) are molecules that can inhibit efflux pumps; they have been considered potential therapeutic agents for rejuvenating the activity of antibiotics that have already lost their activity against bacteria. However, studies are yet to determine the specific substrates for such pumps; the effect of altered efflux activity of these pumps on biofilm formation is still being investigated. A clear knowledge of the involvement of efflux pumps in biofilm development could aid in developing new agents that can interfere with their function and help to prevent biofilms formation; thereby, improving the outcome of treatment strategies. This review focuses on the novel update of EPIs and discusses the evidence of the roles of efflux pumps in biofilm formation; the potential approaches towards overcoming the increasing problem of biofilm-based infections are also discussed.
The Role of Nanoparticles in the Inhibition of Multidrug-Resistant Bacteria and Biofilms

AlMatar M, Makky EA, Var I, Koksal F

Curr Drug Deliv, 2018;15(4):470-484.
PMID: 29219055 DOI: 10.2174/1567201815666171207163504

BACKGROUND: Until recently, one of the main reasons for mortality has been infectious diseases, and bacteria that are drug-resistant have emerged as a result of the wide application, as well as the misuse of antibacterial medications. Having multidrug-resistance, bacteria present a great problem for the efficient management of bacterial infections and this challenge has resulted in the creation of other means of dealing with bacterial diseases. Of late, metallic nanoparticles (NPs), employed as antibacterial agents, have the potential for use against resistance to bacterial drugs.
OBJECTIVE: The mechanisms of bacterial resistance are described in this review and this is followed by an outline of the features and uses of metallic NPs as antibiotic agents to address bacteria that are antibiotic- sensitive and resistant. Additionally, a general impression of metallic NPs as antibiofilm bactericidal agents is presented.
CONCLUSION: Biofilms and bacterial strains that are resistant to antibiotics present a grave public health challenge and this has enhanced the need to develop new bactericidal agents. Therefore, nanomaterials are considered as a potential platform for managing bacterial infections.
Insights into the Structural Complexities of SARS-CoV-2 for Therapeutic and Vaccine Development

AlMatar M, Ramli ANM, Albarri O, Yi CX

Comb Chem High Throughput Screen, 2023;26(11):1945-1959.
PMID: 36366840 DOI: 10.2174/1386207326666221108095705

SARS-CoV-2 is a disease that endangers both human life and the economy. There was an 11- month period of relative evolutionary standstill following the appearance of SARS-CoV-2 in late 2019. However, the emergence of clusters of mutations known as' variants of concern 'with variable viral properties such as transmissibility and antigenicity defined the evolution of SARS-CoV-2. Several efforts have been made in recent months to understand the atomic level properties of SARS-CoV-2. A review of the literature on SARS-CoV-2 mutations is offered in this paper. The critical activities performed by different domains of the SARS-CoV-2 genome throughout the virus's entry into the host and overall viral life cycle are discussed in detail. These structural traits may potentially pave the way for the development of a vaccine and medication to combat the SARS-CoV-2 sickness.
Are There Any Other Compounds Isolated From Dermacoccus spp at All?

AlMatar M, Eldeeb M, Makky EA, Köksal F, Var I, Kayar B

Curr Microbiol, 2017 Jan;74(1):132-144.
PMID: 27785553 DOI: 10.1007/s00284-016-1152-3

Microbial-derived natural products have functional and structural diversity and complexity. For several decades, they have provided the basic foundation for most drugs available to modern medicine. Microbial-derived natural products have wide-ranging applications, especially as chemotherapeutics for various diseases and disorders. By exploring distinct microorganisms in different environments, small novel bioactive molecules with unique functionalities and biological or biomedical significance can be identified. Aquatic environments, such as oceans or seas, are considered to be sources of abundant novel bioactive compounds. Studies on marine microorganisms have revealed that several bioactive compounds extracted from marine algae and invertebrates are eventually generated by their associated bacteria. These findings have prompted intense research interest in discovering novel compounds from marine microorganisms. Natural products derived from Dermacoccus exhibit antibacterial, antitumor, antifungal, antioxidant, antiviral, antiparasitic, and eventually immunosuppressive bioactivities. In this review, we discussed the diversity of secondary metabolites generated by genus Dermacoccus with respect to their chemical structure, biological activity, and origin. This brief review highlights and showcases the pivotal importance of Dermacoccus-derived natural products and sheds light on the potential venues of discovery of new bioactive compounds from marine microorganisms.
Does the Development of Vaccines Advance Solutions for Tuberculosis?

AlMatar M, Makky EA, AlMandeal H, Eker E, Kayar B, Var I, et al.

Curr Mol Pharmacol, 2019;12(2):83-104.
PMID: 30474542 DOI: 10.2174/1874467212666181126151948

BACKGROUND: Mycobacterium tuberculosis (Mtb) is considered as one of the most efficacious human pathogens. The global mortality rate of TB stands at approximately 2 million, while about 8 to 10 million active new cases are documented yearly. It is, therefore, a priority to develop vaccines that will prevent active TB. The vaccines currently used for the management of TB can only proffer a certain level of protection against meningitis, TB, and other forms of disseminated TB in children; however, their effectiveness against pulmonary TB varies and cannot provide life-long protective immunity. Based on these reasons, more efforts are channeled towards the development of new TB vaccines. During the development of TB vaccines, a major challenge has always been the lack of diversity in both the antigens contained in TB vaccines and the immune responses of the TB sufferers. Current efforts are channeled on widening both the range of antigens selection and the range of immune response elicited by the vaccines. The past two decades witnessed a significant progress in the development of TB vaccines; some of the discovered TB vaccines have recently even completed the third phase (phase III) of a clinical trial.
OBJECTIVE: The objectives of this article are to discuss the recent progress in the development of new vaccines against TB; to provide an insight on the mechanism of vaccine-mediated specific immune response stimulation, and to debate on the interaction between vaccines and global interventions to end TB.
Polysaccharides to combat viruses (Covid-19) and microbes: New updates

AlMatar M, Makky EA, Ramli ANM, Kafkas NE, Köksal F

Curr Mol Pharmacol, 2022 Jan 12.
PMID: 35023463 DOI: 10.2174/1874467215666220112150332

COVID-19, which is speedily distributed across the world and presents a significant challenge to public health, is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Following MERS coronavirus (MERS-CoV) and SARS, this is the third severe coronavirus outbreak in less than 20 years. To date, there are no exact agents and vaccines available for the treatment of COVID-19 that are clinically successful. Antimicrobial medications are effective in controlling infectious diseases. However, the extensive use of antibiotics makes microbes more resistant to drugs and demands novel bioactive agents' development. Polysaccharides are currently commonly used in the biomedical and pharmaceutical industries for their remarkable applications. Polysaccharides appear to have a wide range of anti-virus (anti-coronavirus) and antimicrobial applications. Polysaccharides are able to induce bacterial cell membrane disruption as they demonstrate potency in binding onto the surfaces of microbial cells. Here, the antiviral mechanisms of such polysaccharides and their success in the application of antiviral infections are reviewed. Additionally, this report provides a summary of current advancements of well-recognized polysaccharides as antimicrobial and anti-biofilm agents.
Antimicrobial peptides as an alternative to anti-tuberculosis drugs

AlMatar M, Makky EA, Yakıcı G, Var I, Kayar B, Köksal F

Pharmacol Res, 2018 02;128:288-305.
PMID: 29079429 DOI: 10.1016/j.phrs.2017.10.011

Tuberculosis (TB) presently accounts for high global mortality and morbidity rates, despite the introduction four decades ago of the affordable and efficient four-drugs (isoniazid, rifampicin, pyrazinamide and ethambutol). Thus, a strong need exists for new drugs with special structures and uncommon modes of action to effectively overcome M. tuberculosis. Within this scope, antimicrobial peptides (AMPs), which are small, cationic and amphipathic peptides that comprise a section of the innate immune system, are currently the leading potential agents for the treatment of TB. Many studies have recently illustrated the capability of anti-mycobacterial peptides to disrupt the normal mycobacterial cell wall function through various modes, thereby interacting with the intracellular targets, as well as encompassing nucleic acids, enzymes and organelles. This review presents a wide array of antimicrobial activities, alongside the associated properties of the AMPs that could be utilized as potential agents in therapeutic tactics for TB treatment.
The Physiological/Pathophysiological Significance of Vitamin D in Cancer, Cardiovascular Disorders and Beyond

AlMatar M, AlMandeal H, Makky EA, Kayar B, Yarar E, Var I, et al.

Curr Drug Metab, 2017;18(3):207-224.
PMID: 27928943 DOI: 10.2174/1389200217666161207161212

BACKGROUND: Vitamin D, a molecular precursor of the potent steroid hormone calcitriol, has crucial functions and roles in physiology and pathophysiology. Tellingly, calcitriol has been shown to regulate various cellular signalling networks and cascades that have crucial role in cancer biology and diagnostics. Mounting lines of evidences from previous clinical and preclinical investigations indicate that the deficiency of vitamin D may contribute to the carcinogenesis risk. Concomitantly, recent reports suggested that significant reduction in the cancer occurrence and progression is more likely to appear after vitamin D supplementation. Furthermore, a pivotal role functioned by vitamin D in cardiovascular physiology indicates that the deficiency of vitamin D is significantly correlated with enhanced prevalence of stroke, hypertension and myocardial infarction. Notably, vitamin D status is more likely to be used as a lifestyle biomarker, since poor and unhealthy lifestyles are correlated with the deficiency of vitamin D, a feature which may result in cardiovascular complications. Moreover, recent reports revealed that the effect of vitamin D is to cover not only cardiovascular system but also skeletal system.
OBJECTIVE: Herein, we are highlighting the recent knowledge of vitamin D roles and functions with respect to pathophysiological disorders such as cancer, cardiovascular diseases, rheumatoid arthritis (RA) and debate the potential avails of vitamin D on slowing cancer, cardiovascular disease and RA progression.
CONCLUSION: The findings of this review confirm that the importance of vitamin D metabolites or analogues which can provide a helpful platform to target some kinds of cancer, particularly when used in combination with existing therapies. Moreover, the correlation between vitamin D deficiencies with cardiovascular diseases and rheumatoid arthritis (RA) progression might suggest a pivotal role of vitamin D in either initiation or progression of these diseases.
Fulltext Evaluation of the Antioxidant and Antimicrobial Activities of Ethyl Acetate Extract of Saccharomyces cerevisiae

Makky EA, AlMatar M, Mahmood MH, Ting OW, Qi WZ

Food Technol Biotechnol, 2021 Jun;59(2):127-136.
PMID: 34316274 DOI: 10.17113/ftb.59.02.21.6658

RESEARCH BACKGROUND: Antioxidants are important compounds present at low concentrations that inhibit oxidation processes. Due to the side effects of synthetic antioxidants, research interest has increased considerably towards finding natural sources of antioxidants that can replace the synthetic ones. The emergence and spread of antibiotic resistance require the development of new drugs or some potential sources of novel medicine. This work aims to extract the secondary metabolites of Saccharomyces cerevisiae using ethyl acetate as a solvent and to determine the antioxidant and antimicrobial activities of these extracted metabolites.
EXPERIMENTAL APPROACH: The antioxidant activity of the secondary metabolites of S. cerevisiae were determined using DPPH, ABTS and FRAP assays. Furthermore, the antimicrobial potential of the ethyl acetate extract of S. cerevisiae against Cutibacterium acnes, Staphylococcus aureus and Staphylococcus epidermidis was assessed.
RESULTS AND CONCLUSION: Five out of 13 of the extracted secondary metabolites were identified as antioxidants. The antioxidant activity of the S. cerevisiae extract exhibited relatively high IC50 of 455.26 and 294.51 μg/mL for DPPH and ABTS respectively, while the obtained FRAP value, expressed as ascorbic acid equivalents, was 44.40 μg/mL. Moreover, the extract had a significant antibacterial activity (p<0.05) against Staphylococcus aureus and Staphylococcus epidermidis at the concentrations of 100 and 200 mg/mL, respectively. However, no inhibitory effect was observed against Cutibacterium acnes as the extract was only effective against the bacterium at the concentrations of 300 and 400 mg/mL (inhibition zones ranging from 9.0±0.0 to 9.3±0.6) respectively (p<0.05). Staphylococcus aureus was highly sensitive to the extract, with a MIC value of 18.75 mg/mL.
NOVELTY AND SCIENTIFIC CONTRIBUTION: This report confirmed the efficacy of the secondary metabolites of S. cerevisiae as a natural source of antioxidants and antimicrobials and suggested the possibility of employing them in drugs for the treatment of infectious diseases caused by the tested microorganisms.

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