Binding of the Highly Toxic Tetracycline Derivative, Anhydrotetracycline, to Bovine Serum Albumin

Abstract

Tetracycline (TC) derivatives comprise a group of bacteriostatic antibiotics extensively used in human and veterinary medicine and in acquaculture, and as animal growth promoters due to their safe toxicological profile.1) More recently, they have been proposed as anti-amyloidogenic drugs since they can interfere with protein conformational changes and self-assemblies associated with protein misfolding and deposition diseases. 2-4)Despite their popular use, TC derivatives are highly unstable and some degradation products formed during the storage or normal use of the drugs are pharmacologically toxic or inactive compounds.5) Anhydrotetracycline (AHTC) is one of the major degradation products of TC that has been linked to several side effects of the drug, e.g., cutaneous phototoxicity 6) and Fanconi-type syndrome. 7) AHTC has also proven to be more toxic than TC against environmentally relevant bacteria. 8)AHTC can be produced by dehydration in acid media, 5,8) by photolysis in mild reducing conditions 6,9,10) or during high-temperature treatments.11) Removal of a water molecule from the C5a-C6 positions of TC by treatment with warm mineral acid gives the anhydroderivative (Fig. 1).12) Dehydration leads to significant changes in aromatization and planarity of the tetracyclic moiety, 13,14) showing variations in potency, 15) mechanism of action 1) and lipophilicity 16,17) as compared to the parent compound. Changes in chemical configuration can also modulate the interaction of drugs with serum proteins. 18)Serum albumins are the main carriers of physiological metabolites and pharmacological drugs in blood. Protein binding has a significant impact on the pharmacokinetics and biological activity of drugs and modulates the toxicity of bound substances, attenuates adverse reactions and prolongs the in vivo half-life of therapeutic agents. 18-21)The facts outlined above prompted us to investigate the interaction of AHTC with bovine serum albumin (BSA) using three biophysical techniques. Binding affinity and number of interacting ligands were assessed by fluorimetric titration. . Drug binding was enthalpically and entropically driven and seemed to involve hydrophobic interactions. AHTC fluorescence enhancement and hypsochromic shifts observed upon binding suggested a low-polarity location excluded from water for the bound drug. Our data are useful for evaluating the biodisponibility of the pharmacophore and the dynamic distribution of the toxic derivative.

Insights into the interactions between tetracycline, its degradation products and bovine serum albumin

“…In contrast, the action of ATC enhanced the polarity of the fluorophore microenvironment of BSA and decreased its hydrophobicity. Thus, the maximum emission wavelength of the ATC-BSA system underwent a red shift from 341.4 to 346.4 nm, consistent with the result of Burgos et al ( 2011 ), indicating that there is an elimination reaction of a water molecule between the alcohol hydroxyl of C6 and the hydrogen of C5a, leading to a difference in the TC molecular structure. Thus, the effects of ATC, TC, and ETC on the BSA fluorescence chromophore microenvironment were different.…”

Cytotoxicity Induced by Tetracyclines via Protein Photooxidation

“…The graph in Figure 1 shows that the affinity between the molecules and BSA increases with lipophilicity: tetracycline > meclocycline > oxytetracycline. That rate of affinity shown in Figure 1 is in accordance with the literature data [27][28][29][30][31].…”

The Role of Antibiotic-Target-Modifying and Antibiotic-Modifying Enzymes in Mycobacterium abscessus Drug Resistance

“…While this finding together with the severe side effects associated with ATc use, makes it an unattractive drug candidate, it nevertheless represents a flexible starting point for developing MabTetX inhibitors with improved activity, better tolerability and minimal binding affinity towards MabTetR x . Co-administration with a potent MabTetX monooxygenase inhibitor can potentially rescue the clinical efficacies of tetracycline and doxycycline which are currently inactive against the M. abscessus complex ( Burgos et al, 2011 ; Rudra et al, 2018 ).…”