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Fungal Enzymes in Organic Pollutants Bioremediation
Published in Pankaj Bhatt, Industrial Applications of Microbial Enzymes, 2023
Adam Grzywaczyk, Wojciech Smułek, Jakub Zdarta, Ewa Kaczorek
When discussing the uses of fungi, the production of antibiotics must be mentioned. Penicillin was the first isolated antibiotic, by Alexander Fleming, almost 100 years ago, in 1928, from Penicillium notatum. The mechanism of action of penicillins as antibiotics is based on blocking the activity of bacterial enzymes called transpeptidases (PBP) involved in the final stage of peptidoglycan synthesis in the bacterial cell wall (Soares et al., 2012). The source of another important antibiotic, cephalosporin, was the fungus Cephalosporium acremonium. The action of this antibiotic is similar to that of penicillin; they covalently bind to the active center of bacterial enzymes: carboxypeptidases and transpeptidases, blocking their action. Thus, they inhibit the process of bacterial cell wall synthesis (Bhide et al., 2020; Yotsuji et al., 1988). Both penicillin and cephalosporin belong to the group of β-lactam antibiotics. Another example is griseofulvin, obtained in 1939 from Penicillium griseofulvum. Interestingly, it has antifungal properties against Trichophyton, Microsporum, and Epidermophyton species and was the first oral antifungal drug used in the treatment of dermatomycoses (Bai et al., 2019; Gupta et al., 2018). Structures of penicillin and cephalosporin are presented in Figure 6.5.
Mechanism of Drug Resistance in Staphylococcus aureus and Future Drug Discovery
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Felipe Wakasuqui, Ana Leticia Gori Lusa, Sven Falke, Christian Betzel, Carsten Wrenger
The first class, the ß-lactams antibiotics are broad-spectrum bactericidal, which act by inhibiting the biosynthesis of the peptidoglycan layer of the bacterial cell wall, affecting its integrity. They are analogues of the d-alanyl-d-alanine, the terminal amino acid residues on the precursor peptide subunits of the nascent peptidoglycan layer; and they bind to the Ser residue of the dd-transpeptidase, commonly called penicillin binding proteins (PBPs), the enzyme responsible for the final cross-linking of the peptidoglycan layer (Bush and Bradford, 2016). Today two mechanism of resistance to ß-lactams chemotherapy are known: the plasmid acquired gene blaZ, that encodes for a ß-lactamase enzyme, which cleaves the ß-lactam ring of penicillins, preventing their effect; and the mecA gene, which codes a transpeptidase with much lower affinity for ß-lactams (Lowy, 2003). Penicillinase activity can be overcome by the addition of a beta-lactamase inhibitor or use of a penicillinase-resistant penicillin (e.g., oxacillin, nafcillin), but mecA provides S. aureus a broad protection against ß-lactams. The mecA is located in a mobile genetic element called staphylococcal cassette chromosome (SCC), which is a transposonlike element exclusively used among staphylococcal species to share genes useful to survive in adverse environment, therefore many antibiotics resistance genes can be found within SCC (Hiramatsu, et al., 2014b). Despite its narrow effect of protection, blaZ has an important regulatory role in S. aureus carrying mecA. Bla regulators not only stabilize the mecA acquisition, but also works as an anti-repressor in mecA locus, and overexpression of bla regulators enhance ß-lactams in mecA containing MRSA strains (Arêde et al., 2013). Rare strains remain susceptible to ß-lactams, but in these uncommon cases the ß-lactams oxacillin and nafcillin are preferred option, except for treating pneumonia (Auwaeter, 2018).
β-Lactams and Related Compounds as Antibacterials and β-Lactamase Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Ulrike Holzgrabe, Jens Schmitz
With the launch of every new anti-infective drug, the bacteria have learnt to fight against the new compounds. There are various mechanisms causing the resistance: For the entry of β-lactam antibiotic into the periplasma of the bacteria outer membrane, porine proteins are necessary. These porine channels can be deleted by the bacteria. Moreover, if the β-lactams have reached the periplasma already, bacteria are able to express single- and multi-component efflux pumps, which very effectively deport the antibiotics out of the cell (Li et al., 2015). Both mechanisms substantially decrease the concentration of the β-lactam in the bacteria cells.Moreover, Gram-positive bacteria develop new PBPs showing mutations in the active site (see MRSA) in order to evade the inhibition by the β-lactams. Alternatively, an intrinsically resistant PBP can be acquired from the neighbor bacterium, by means of a horizontal transfer of the genes (conjugation or transduction), and substitute the PBP, which is irreversibly inhibited by a β-lactam antibiotic.Gram-negative pathogens express β-lactamases, which deactivate the β-lactam by hydrolysis of the four-membered β-lactam ring. Such lactamases were already reported in 1940 in Nature by Abraham and Chain shortly after the invention of benzylpenicillin. They were isolated from E. coli before penicillins were used in clinical settings. Meantime an explosion in the number of β-lactamases has occurred. Due to the evolutionary pressure, approximately 1000 β-lactamases are known to date, some of them show an extended-spectrum of hydrolytic activity and are, therefore, named “extended-spectrum β-lactamases (ESBL).” Moreover, bacteria tend to collect multiple β-lactamases in order to be able to hydrolyze a broad range of different β-lactam antibiotics. Furthermore, β-lactamases expression is no longer limited to Gram-negative bacteria nowadays.
Structural effects of nanoparticles on their antibacterial activity against multi-drug resistance
Published in Inorganic and Nano-Metal Chemistry, 2022
Bharti Goyal, Neelam Verma, Tannu Kharewal, Anjum Gahlaut, Vikas Hooda
It is the most common resistance mechanism for naturally originated antibiotics. Polycationic aminoglycosides antibiotics such as kanamycin, tobramycin, and amikacin bind to A site of 30S ribosomal subunits and impair translation. Aminoglycoside-resistant strains possess a plasmid encoding for aminoglycoside phosphorylase, which deactivate aminoglycosides by altering the net positive charge on these antibiotics.[23]S. aureus developed resistance against beta-lactams. It expresses an enzyme named β-lactamase, coded by a plasmid gene, which cleaves the lactam ring of antibiotics.[24] ESKAPE microorganisms produce carbapenemase enzymes (CRE), provide resistance against beta-lactam antibiotics. Beta lactams act on penicillin-binding proteins (PBP) and inhibit peptidoglycan crosslinking in the cell wall. Carbapenem-resistant gram-negative bacteria produce carbapenemase, which cleaves the beta-lactam ring.[25] Carbapenemase includes different classes: Class A- K. pneumoniae carbapenemase (KPC),[26] Class B Metallo-beta-lactamase (MBL). The most famous Verona integron-encoded MBL and New Delhi MBL are categorized into Class B1,[27] Oxacillinase (OXA) included in class D. [28]
Exploring the therapeutic potentials of phyto-mediated silver nanoparticles formed via Calotropis procera (Ait.) R. Br. root extract
Published in Journal of Experimental Nanoscience, 2020
Suresh Sagadevan, Selvaraj Vennila, Lakshmipathy Muthukrishnan, K. Gurunathan, Won Chun Oh, Suriati Paiman, Faruq Mohammad, Hamad A. Al-Lohedan, Ainil Hawa Jasni, Is Fatimah, Kuppan Sivaranjan, Prasanna Kumar Obulapuram
It was inferred from earlier reports that β-lactam antibiotics mimics d-alanylalanine peptide fragment, an enzyme-substrate that facilitates the binding of penicillin-binding proteins (PBPs). These PBPs are found anchored in the cell membrane and are involved in the cross-linking of the bacterial cell wall. The antibiotic irreversibly binds to the active site of PBP disrupting cell wall synthesis. As there is a complete absence of such membranous architecture and enzyme machinery in human cells, antibiotics could not harm them [33].