β-lactam antibiotics are among the most important and widely used antimicrobials worldwide and are comprised of a large family of compounds, obtained by chemical modifications of the common scaffolds. Usually these modifications include the addition of active groups, but less frequently, molecules were synthesized in which either two β-lactam rings were joined to create a single bifunctional compound, or the azetidinone ring was joined to another antibiotic scaffold or another molecule with a different activity, in order to create a molecule bearing two different pharmacophoric functions. In this review, we report some examples of these derivatives, highlighting their biological properties and discussing how this strategy can lead to the development of innovative antibiotics that can represent either novel weapons against the rampant increase of antimicrobial resistance, or molecules with a broader spectrum of action.

We present the synthesis and biological evaluation of the prototype of a new class of cephalosporins, containing an additional isolated beta lactam ring with two phenyl substituents. This new compound is effective against Gram positive microorganisms, with a potency similar to that of ceftriaxone, a cephalosporin widely used in clinics and taken as a reference, and with no cytotoxicity against two different human cell lines, even at a concentration much higher than the minimal inhibitory concentration tested. Additionally, a deep computational analysis has been conducted with the aim of understanding the contribution of its moieties to the binding energy towards several penicillin-binding proteins from both Gram positive and Gram negative bacteria. All these results will help us developing derivatives of this compound with improved chemical and biological properties, such as a broader spectrum of action and/or an increased affinity towards their molecular targets.

Background One of the main concerns of the modern medicine is the frightening spread of antimicrobial resistance caused mainly by the misuse of antibiotics. The researchers worldwide are actively involved in the search for new classes of antibiotics, and for the modification of known molecules in order to face this threatening problem. We have applied a computational approach to predict the interactions between a new cephalosporin derivative containing an additional β-lactam ring with different substituents, and several serine β-lactamases representative of the different classes of this family of enzymes. Results The results of the simulations, performed by using a covalent docking approach, has shown that this compound, although able to bind the selected β-lactamases, has a different predicted binding score for the two β-lactam rings, suggesting that one of them could be more resistant to the attack of these enzymes and stay available to perform its bactericidal activity. Conclusions The detailed analysis of the complexes obtained by these simulations suggests possible hints to modulate the affinity of this compound towards these enzymes, in order to develop new derivatives with improved features to escape to degradation. Electronic supplementary material The online version of this article (10.1186/s12900-018-0092-5) contains supplementary material, which is available to authorized users.

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The third step of the catabolism of galactose in mammals is catalyzed by the enzyme galactose-1-phosphate uridylyltransferase (GALT), a homodimeric enzyme with two active sites located in the proximity of the intersubunit interface. Mutations of this enzyme are associated to the rare inborn error of metabolism known as classic galactosemia; in particular, the most common mutation, associated with the most severe phenotype, is the one that replaces Gln188 in the active site of the enzyme with Arg (p.Gln188Arg). In the past, and more recently, the structural effects of this mutation were deduced on the static structure of the wild-type human enzyme; however, we feel that a dynamic view of the proteins is necessary to deeply understand their behavior and obtain tips for possible therapeutic interventions. Thus, we performed molecular dynamics simulations of both wild-type and p.Gln188Arg GALT proteins in the absence or in the presence of the substrates in different conditions of temperature. Our results suggest the importance of the intersubunit interactions for a correct activity of this enzyme and can be used as a starting point for the search of drugs able to rescue the activity of this enzyme in galactosemic patients.

Classic galactosemia is an inborn error of metabolism associated with mutations that impair the activity and the stability of galactose-1-phosphate uridylyltransferase (GALT), catalyzing the third step in galactose metabolism. To date, no treatments (including dietary galactose deprivation) are able to prevent or alleviate the long-term complications affecting galactosemic patients. Evidence that arginine is able to improve the activity of the human enzyme expressed in a prokaryotic model of classic galactosemia has induced researchers to suppose that this amino acid could act as a pharmacochaperone, but no effects were detected in four galactosemic patients treated with this amino acid. Given that no molecular characterizations of the possible effects of arginine on GALT have been performed, and given that the samples of patients treated with arginine are extremely limited for drawing definitive conclusions at the clinical level, we performed computational simulations in order to predict the interactions (if any) between this amino acid and the enzyme. Our results do not support the possibility that arginine could function as a pharmacochaperone for GALT, but information obtained by this study could be useful for identifying, in the future, possible pharmacochaperones for this enzyme.

Pharmacological chaperones are chemical compounds able to bind proteins and stabilize them against denaturation and following degradation. Some pharmacological chaperones have been approved, or are under investigation, for the treatment of rare inborn errors of metabolism, caused by genetic mutations that often can destabilize the structure of the wild-type proteins expressed by that gene. Given that, for rare diseases, there is a general lack of pharmacological treatments, many expectations are poured out on this type of compounds. However, their discovery is not straightforward. In this review, we would like to focus on the computational methods that can assist and accelerate the search for these compounds, showing also examples in which these methods were successfully applied for the discovery of promising molecules belonging to this new category of pharmacologically active compounds.

Für die Untersuchung des Eisenstoffwechsels ist es von Wichtigkeit, festzustellen, inwieweit die Nieren bei der Eisenausscheidung eine Rolle spielen. Die von älteren Autoren gefundenen Werte für die unter physiologischen Verhältnissen in 24 Stunden im Harn ausgeschiedenen Eisenmengen schwankten infolge mangelhafter Methodik beträchtlich. Es wurden bis zu 11 mg Eisen gefanden. 1 ) Später gab Neumann 2 ) die mit einer verbesserten Methode gefundenen Werte für das Harneisen mit durchschnittlich l mg an. In der neuesten Zeit hat sich W. Lintzel 3 ) mit dieser Frage eingehend beschäftigt und auch eine neue colorimetrische Methode ausgearbeitet, welche noch 0,005 mg Eisen in der Analyse zu bestimmen gestattet. Auf Grund seiner Untersuchungen kam er zu dem Schluß, daß im normalen Menschenharn kein Eisen enthalten ist und daß die Niere unter physiologischen Bedingungen als Organ der Eisenausscheidung nicht in Frage kommt. Diese Annahme wurde von Henriques und Rolland 4 ) bestritten, welche mit der Titanmethode 0,08-0,32 mg Eisen pro Tag im Harn fanden. Diese Mengen sind zwar wesentlich geringer als die von früheren Autoren gefundenen, können aber durch Beimengung von Harnepithelien und Leukocyten nicht ohne weiteres erklärt werden. Lintzel 5 ) führt ihre höheren Werte auf gewisse Fehler der von ') W. Lintzel, Ergebnisse d. Physiol. 81, 844(1931). Die Literatur ist dort bis zum Jahre 1929 berücksichtigt und zitiert. 2 )