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New Strategies to Discover Non-Ribosomal Peptides as a Source of Antibiotics Molecules
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Mario Alberto Martínez-Núñez, Zuemy Rodríguez-Escamilla, Víctor López y López
The advance in experimental techniques, such as mass spectrometry, has allowed us to combine the in silico approaches with the experimental ones. An example of these new strategies was the study carried out by Vater et al. (2018); using bioinformatics and mass spectrometry techniques, these authors analyzed the genome of Paenibacillus polymyxa strain E681 to find NRPSs. They detected four gene clusters for the production of NRPs corresponding to four lipopeptide families, encoding fusaricidins, polymyxins, tridecaptins, and a yet unknown lipoheptapeptide designated as paenilipoheptin. These lipopeptides are cyclic compounds which contain a C12–13-beta-amino fatty acid integrated into the peptide ring (Vater et al., 2018). The cyclical structure of the majority of NRPs has made it difficult to identify them using traditional methods that have been developed for the identification of linear peptides; hence, bioinformatics methods have been used to identify them such as NRPquest which couples mass spectrometry and genome mining for the identification of NRPs (Mohimani et al., 2014).
Fibrinolytic Enzymes for Thrombolytic Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Swaroop S. Kumar, Sabu Abdulhameed
Various bacterial species excluding Bacillus sp. and Streptomyces sp. are also reported to produce fibrinolytic enzymes although those two genera contribute most of the fibrinolytic enzymes discovered so far. A 63.3 kDa serine protease was isolated from Paenibacillus polymyxa EJS-3 named PPFE-I. It was found dissolving Aα-chain of fibrinogen quickly and subsequently Bβ-chain and followed by γ-chain during fibrinogenolysis (Lu et al., 2010). Paenibacillus sp. IND8 is also known to produce fibrinolytic enzyme (Vijayaraghavan and Vincent, 2016a). A 50 kDa metalloprotease with thrombolytic effect was reported from Serratia sp. RSPB11 and Serratia sp. KG-2-1 (Lakshmi and Prakasham, 2013; Taneja et al., 2017). Another fibrinolytic enzyme producer is Shewanella sp. IND20 which contributed a 55.5 kDa thrombolytic enzyme (Vijayaraghavan and Vincent, 2015). Psuedoalteromonas sp. IND11 yielded a 64 kDa protease which acted as plasminogen activator and disintegrated blood clot directly (Vijayaraghavan et al., 2015). Treponema denticola also reported with thrombolytic enzyme production (Rosen et al., 1994). Fibrinolytic enzyme from Proteus penneri showed higher affinity towards α-chain followed by β-chain, showing lower affinity towards γ-chain. It leaves partially hydrolyzed γ-chain after fibrinolysis (Jhample et al., 2015). Nattokinase enzyme production was reported from Pseudomonas sp. TKU015 with molecular weight of 24 kDa as determined by gel filtration chromatography (Wang et al., 2009). Bacterial fibrinolytic enzymes other than those from Bacillus sp. and actinomycetes are shown in Table 4.7.
Polymyxins
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
The polymyxins are a group of antibiotics, named A, B, C, D, E, and so on, which were first isolated in 1947 from a spore-bearing soil bacillus (Paenibacillus polymyxa). Although several polymyxins exist, only polymyxin B and E (the latter also known as colistin) are used clinically. The polymyxins, like bacitracin (see Chapter 83, Bacitracin and gramicidin), have a polypeptide structure. The structures of polymyxin B and colistin are shown in Figure 81.1a. Given that both polymyxins are produced by fermentation, it is not surprising that they are a mixture of several components, with two major components for each of polymyxin B and colistin (see Figure 81.1a). Because of the multicomponent nature and the absent or wide limits on the allowed content of the components as specified in the United States and European Pharmacopoeias (European Pharmacopoeia, 2014b, 2015; Nation et al., 2015; US Pharmacopeial Convention, 2016a, 2016b), there is no accurate molecular weight for either polymyxin B or colistin. However, the molecular weights for polymyxin B1, polymyxin B2, colistin A (polymyxin E1), and colistin B (polymyxin E2) are 1202, 1188 (Orwa et al., 2001b), 1170, and 1156 (Li et al., 2001a; Orwa et al., 2001a), respectively. Clinically, polymyxin B is administered parenterally as its sulfate salt. Although colistin sulfate also exists commercially, this is not the form for parenteral administration. Instead, colistin is administered parenterally in the form of the sodium salt of colistin methanesulfonate (CMS) (also known as colistimethate). It is important to note that the methanesulfonate of colistin is not a salt as such; it is a chemical derivative in which methanesulfonate moieties are attached through covalent bonds to the primary amines in colistin (Figure 81.1b). The structure shown in the figure has one methanesulfonate moiety attached to each of the five primary amines of colistin; this has been the perceived structure of CMS for decades. However, recent studies have revealed greater chemical complexity. Some primary amines may not be derivatized, whereas others may have two methanesulfonate groups attached (Kenyon, 2015). The United States and European Pharmacopoeias do not specify limits for the numerous possible components of CMS (European Pharmacopoeia, 2014a; Nation et al., 2015; US Pharmacopeial Convention, 2016b). Polymyxin B and colistin are cationic (by virtue of the primary amines that are ionized [i.e. carry positive charges] at physiologic pH). In contrast, CMS is anionic [by virtue of the methanesulfonate groups which are ionized (i.e. carry negative charges) at physiological pH]. As discussed later and in section 2, Antimicrobial activity, and section 5, Pharmacokinetics and pharmacodynamics, CMS is an inactive prodrug of colistin (Bergen et al., 2006).
The purification and functional study of new compounds produced by Escherichia coli that influence the growth of sulfate reducing bacteria
Published in Egyptian Journal of Basic and Applied Sciences, 2020
Oluwafemi Adebayo Oyewole, Julian Mitchell, Sarah Thresh, Vitaly Zinkevich
Several studies have described some inhibitors of SRB growth that are derived from bacteria; for example, Jayaraman et al. [69] and Zuo [29] reported that indolicidin, bactenecin, and polymyxin produced by Paenibacillus polymyxa are capable of inhibiting SRB growth. Bacillus brevis produces a compound referred to as gramicidin-S that inhibits the growth of Desulfovibrio orientis, D. vulgaris and D. gigas [29,31,70] and thereby reduced corrosion caused by the SRB. In addition, Bacillus licheniformis secretes γ-polyglutamate and polyaspartate that reduce SRB growth [29,71,72]. The mechanism of SRB growth prevention by these organisms has been suggested and include either the production of antimicrobial agents [29,73] or attack on the adenosine 5ʹ- phosphosulphate (APS) and bisulfate reductase (DSR) responsible for hydrogen sulfide production in SRBs [14]. Similarly, the SGE may function in SRB induction by increasing their growth rate while the SGI may function by causing damage in the cells as observed in this study. The MALDI-TOF spectra showed the presence of low molecular weight compounds in the range of 1700 Da for SGE and 2400 Da for SGI. The spectra showed equal and repeating units of ~213 m/z between the peaks. According to Wallace and Guttman [74], the equal and repeating units are characteristic spectra of condensation homopolymers. MALDI-TOF spectra revealed that the compounds are small molecular weight biomolecules and that the two molecules are very closely related.
Prevention of colistin induced nephrotoxicity: a review of preclinical and clinical data
Published in Expert Review of Clinical Pharmacology, 2021
Fatemeh Jafari, Sepideh Elyasi
Colistin (polymixin E), a broad spectrum antibiotic against gram-negative bacteria, is commonly used in hospitalized patients in the treatment of multidrug resistant (MDR) infections, particularly carbapenem resistant strains. It was first introduced in 1950s, isolated from Paenibacillus polymyxa [1]. It was withdrawn in 1970s due to its high rates of nephrotoxicity [2]. However, it was reintroduced later as a last-line option for life-threatening MDR infections in critically ill patients because of the lack of effective alternative choices [3].
The antifungal activity of caspofungin in combination with antifungals or non-antifungals against Candida species in vitro and in clinical therapy
Published in Expert Review of Anti-infective Therapy, 2022
Shan Su, Haiying Yan, Li Min, Hongmei Wang, Xueqi Chen, Jinyi Shi, Shujuan Sun
Antimicrobial peptides (AMPs) have been investigated as a tremendous potential source of new anti-infective agents, and they are generally non toxic to mammalian cells. Polymyxins, which are produced by Paenibacillus polymyxa, are cationic cyclic heptapeptides. They can interact with the bacterial cytoplasmic membrane and therefore change its permeability and trigger cell death [78]. Caspofungin plus colistin (polymyxin E) was found to act synergistically against five caspofungin-susceptible C. albicans [79] isolates. The MIC of colistin was reduced from 50 µg/ml-250 µg/ml to 0.39 µg/ml −0.78 µg/ml, the MIC of caspofungin was reduced from 0.5–2.0 µg/ml to 0.125–0.5 µg/ml, and the FICI was 0.12–0.26. It was suggested that echinocandin-mediated alteration of the cell wall might facilitate colistin access to and perturbation of fungal membranes, which in turn would facilitate echinocandin activity [79]. The same result was found in mouse models that were infected with the wild-type strain, SC5314 [79]. Additionally, the in vitro activity of caspofungin plus polymyxin B against fluconazole-resistant C. glabrata (n = 7) was tested, and the study showed that this combination exhibited a synergistic effect against four of these strains [80]. Tyrocidine, which is produced by Bacillus aneurinolyticus, was also studied to develop antifungal drugs [81]. The tyrocidine complex exhibited a synergistic effect against biofilms with caspofungin at concentrations ranging from 1.8–6.2 µM, and the FICI was 0.10–0.35. This combination also exhibited antifungal activity in vivo; TrcA (3.0 µM) combined with CAS (0.19 µM) led to a 42 ± 3% survival rate of nematodes after five days, while CAS (0.19 µM) alone led to a 27 ± 3% survival rate [81]. The lipopeptide, PAL-Lys-Lys-NH2, in combination with CAS, showed 14 isolates with synergy and 2 indifferent isolates (87.5% and 12.5%, respectively) [82].