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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.
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.