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Antibiotics: The Need for Innovation
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
A single fluorine atom at position 6 greatly increased activity as well as uptake into the bacterial cell. Addition of a piperazine ring on position 7 is beneficial; improved oral adsorption, tissue distribution, metabolic stability, as well as improving the level and spectrum of activity are among the advantages. Presumably, the ability for the basic substituent to form a zwitterion with the carboxyl group is the reason for these improved drug properties. Further modifications include addition of an isopropyl ring to nitrogen 1, and replacement of pyridine with benzene. This leads to the development of ciprofloxacin, which is regarded as one of the most active broad spectrum antibiotics available. Furthermore, bacteria are slow to develop resistance to it, unlike nalidixic acid.
The Interaction of Lipid A and Lipopolysaccharide with Human Serum Albumin
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
One of the sites on HSA is subdomain IIIA, while the other presumably, is IIIB. At neutral pH, only domain III is zwitterionic with a net charge of 0, while domains I and II have net charges of—10 and—8, respectively (18). Given the anionic nature of LPS and lipid A and the observation that cationicity is a necessary requisite for LPS-binding substances (32,33,37,56), it would appear that domain III would present electrostatically favorable sites for LPS binding. It is to be noted that this region of HSA has several highly basic arginine residues (57). A more precise understanding of the nature of endotoxin binding could potentially come from studying other members of the albumin family; a-fetoprotein, an albumin-related transport protein that shares a 39% homology with HSA lacks the double disulfide bridge in subdomain IIA, and vitamin d-binding protein, yet another member of the albumin family, lacks subdomain IIIB almost entirely (28). A novel 87 kDa protein with a domain structure similar to that of the albumins called afamin has recently be identified (58). A comparative study of LPS binding with these proteins may help better conceptualize the structural determinants that govern LPS binding in these proteins.
Infrared Spectroscopy
Published in Adorjan Aszalos, Modern Analysis of Antibiotics, 2020
Preti and Tosi [85] have observed that there is considerable intorest in the effect of metal ions on antibacterial activity and on the rate of hydrolysis of the β-lactam ring in penicillins, and that group 8B complexes, especially those of radium, iridium, and platinum, have been reported to have considerable antibacterial power and induce lysis in lysogenic bacteria. Additionally, there is interest in metal complexes as dosage forms, as part of a sustained release formulation or as a form that would be less toxic. The authors studied the complexes of Cr(III), Mn(II), Rh(III), and Ir(III) with the antibiotic cycloserine. This compound exists as a zwitterion. Assignments were made using a model compound in which the NH2 function was missing, thus permitting no zwitterionic equilibrium. With Cr(III), 1:3 and 1:6 complexes were formed. With Mn(II), 1:4 complexes resulted, but Rh(III) and Ir(III) yielded 1:3 complexes. In Cr(III) 1:6 complexes and Mn(II) complexes, vibrational modes due to NH2, NH, and NH3+ are still present. The C=0 bands are intense and shifted to lower frequencies by about 70—90 cm−1. This implies that the C=0 oxygen is the donor center of the ligand and that the zwitterionic form is still present even in the ligand.
Orally administered intelligent self-ablating nanoparticles: a new approach to improve drug cellular uptake and intestinal absorption
Published in Drug Delivery, 2022
Yanzi Liang, Ruihuan Ding, Huihui Wang, Lanze Liu, Jibiao He, Yuping Tao, Zhenyu Zhao, Jie Zhang, Aiping Wang, Kaoxiang Sun, Youxin Li, Yanan Shi
Oral drug administration is the most commonly used method of drug administration as the drugs used during the method are portable. The harsh acidic environment of the stomach, extensive enzymatic degradation in the presence of various enzymes, and the process of mucus clearance reduce the efficiency of the method (Fan et al., 2018). Therefore, nanocarriers designed for oral administration should be able to promote mucus permeation and epithelial absorption, although these two processes require significantly different carrier properties (Liu et al., 2016; Drucker, 2020). Hence, oral drug delivery systems are being increasingly studied. Commonly used Polyethylene glycol-modified nanoparticles have hydrophilic and near-neutrally charged surfaces that reduce the mucus adhesion by hindering hydrophobic or electrostatic interactions (Khutoryanskiy, 2018; Nie et al., 2019). It has been recently reported that a zwitterionic carrier platform can be used to simultaneously surmount the mucus and epithelial barriers. The use of zwitterions significantly increases the rate of protein payload transport. Moreover, the zwitterionic systems do not exhibit immune response, unlike Polyethylene glycol (PEG) (Xu et al., 2018; Debayle et al., 2019; Han et al., 2020). Zwitterionic polymers that are electrically neutral but bear identical cationic and anionic groups have attracted immense attention from researchers working in the field of biomedicine. Phosphorylcholine, carboxybetaine, and sulfobetaine are the most widely used systems (Peng et al., 2020; Bevilacqua et al., 2021).
Intestinal permeation enhancers to improve oral bioavailability of macromolecules: reasons for low efficacy in humans
Published in Expert Opinion on Drug Delivery, 2021
Sam Maher, Caroline Geoghegan, David J. Brayden
The physicochemical properties of the PE and macromolecule must also be considered an area for optimization, as are the properties of the formulation. Although the majority of macromolecules may exhibit properties similar to BCS Class III drugs, exhibiting high solubility and low permeability, an assumption that solubility and dissolution are not key factors in development of oral formulations may not be accurate. Macromolecule drugs are often ionizable containing both acidic and basic side chains, and in some cases display amphipathic and zwitterionic behaviors, which has a significant impact on release properties in environments of high ionic strength. Zwitterionic peptides and proteins exhibit their lowest solubility at their pI. They are slow to dissolve at this pH and can precipitate if the bulk intestinal fluid has a high ionic strength or if there are divalent cations. Many peptides have good solubility in acidic conditions, but poor dissolution characteristics at the pH range in the small intestine (pH 6 to 7.5). Insulin is practically insoluble in water at its pI (5.4), but dissolves well at < pH 4 [183]. Insulin dissolves to a capacity of 5 mg/mL in water at pH 7, although solubility can decrease in the presence of organic species, electrolytes, and/or Zn2+ and Ca2+.
Preformulation studies of l -glutathione: physicochemical properties, degradation kinetics, and in vitro cytotoxicity investigations
Published in Drug Development and Industrial Pharmacy, 2020
Mengyang Liu, Manisha Sharma, Guo-Liang Lu, Naibo Yin, Murad Al Gailani, Sree Sreebhavan, Jingyuan Wen
The pH level of the solution affects the chargeability of GSH, where the charge of the zwitterion would change according to different pH values. When the pH of the external solution is higher than the pH of the zwitterion, the zwitterion will release a proton and acquire a negative charge. When the pH of the external solution is lower than the pH of the zwitterion, the zwitterion undergoes protonation and becomes positively charged [35]. The isoelectric point (pI) is the pH at which the positive and negative charge values of the zwitterion are equal, and it is an important parameter for formulation design [36]. The charged nature of GSH is related to its pI value, resulting in the complex dissociation equilibrium of GSH in aqueous solution as shown in Figure 9 [35]. GSH± is the main form of GSH at the isoelectric pH, so the value of pI can be calculated based on theoretical approximation count pI = [pK1(COOH)+pK2(COOH)]/2 = 2.79, which is consistent with the literature value of 2.89 [37].