1. Investigación

In this paper, molecular topology was used to develop a mathematical model capable of classifying compounds according to their antibacterial activity. Topological indices were used as structural descriptors and their relation to antibacterial activity was determined by applying linear discriminant analysis (LDA) on a group of quinolones, widely used nowadays because of their broad spectrum of activity, well tolerance profile and advantageous pharmacokinetic properties. The topological model of activity obtained included two discriminant functions, selected by a combination of various statistical paremeters such as Fisher-Snedecor F and Wilk's lambda, and allows the reliable prediction of antibacterial activity in any organic compound. After a virtual pharmacological screening on a library of 6375 compounds, the model has selected 263 as active compounds, from which 40% have proven antibacterial activity. The results obtained clearly reveal the high efficiency of molecular topology for the prediction of pharmacological activities. These models are very helpful in the discovery of new applications of natural and synthetic molecules with different chemical or biological properties. Therefore, we finally present 158 strong candidates to be developed as novel antibacterials.

Molecular topology was used to develop a mathematical model capable of classifying compounds according to antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA). Topological indices were used as structural descriptors and their relation to antimicrobial activity was determined by using linear discriminant analysis. This topological model establishes new structure activity relationships which show that the presence of cyclopropyl, chlorine and ramification pairs at a distance of two bonds favor this activity, while the presence of tertiary amines decreases it. This model was applied to a combinatorial library of a thousand and one 6-fluoroquinolones, from which 117 theoretical active molecules were obtained. The compound 10 and five new quinolones were tested against MRSA. They all showed some activity against MRSA, although compounds 6, 8 and 9 showed anti-MRSA activity similar to ciprofloxacin. This model was also applied to 263 theoretical antibacterial agents described by us in a previous work, from which 34 were predicted as theoretically active. Anti-MRSA activity was found bibliographically in 9 of them (ensuring at least 26% of success), and from the rest, 3 compounds were randomly chosen and tested, finding mitomycin C to be more active than ciprofloxacin. The results demonstrate the utility of the molecular topology approaches for identifying new drugs active against MRSA.

Fluorimetric analysis is still a growing line of research in the determination of a wide range of organic compounds, including pharmaceuticals and pesticides, which makes necessary the development of new strategies aimed at improving the performance of fluorescence determinations as well as the sensitivity and, especially, the selectivity of the newly developed analytical methods. In this paper are presented applications of a useful and growing tool suitable for fostering and improving research in the analytical field. Experimental screening, molecular connectivity and discriminant analysis are applied to organic compounds to predict their fluorescent behaviour after their photodegradation by UV irradiation in a continuous flow manifold (multicommutation flow assembly). The screening was based on online fluorimetric measurement and comprised pre-selected compounds with different molecular structures (pharmaceuticals and some pesticides with known 'native' fluorescent behaviour) to study their changes in fluorescent behaviour after UV irradiation. Theoretical predictions agree with the results from the experimental screening and could be used to develop selective analytical methods, as well as helping to reduce the need for expensive, time-consuming and trial-and-error screening procedures.

Quinolones are one of the most extensively used therapeutic families of antibiotics. However, the increase in antibiotic-resistant bacteria has rendered many of the available compounds useless. After applying our prediction model of activity against E. coli to a library of 1000 quinolones, two quinolones were selected to be synthesized. Additionally, a series of zwitterionic quinolonates were also synthesized. Quinolones and zwitterionic quinolonates were obtained by coupling the corresponding amine with reagent 1 in acetonitrile. Antibacterial activity was assessed using a microdilution method. All the compounds presented antibacterial activity, especially quinolones 2 and 3, selected by the prediction model, which had broad-spectrum activity. Furthermore, a new type of zwitterionic quinolonate with antibacterial activity was found. These compounds can lead to a new line of antimicrobials, as the structures, and, therefore, their properties, are easily adjustable in the amine in position 4 of the pyridine ring.

Currently, the development of resistance of Enterobacteriaceae bacteria is one of the most important health problems worldwide. Consequently, there is a growing urge for finding new compounds with antibacterial activity. Furthermore, it is very important to find antibacterial compounds with a good pharmacokinetic profile too, which will lead to more efficient and safer drugs. In this work, we have mathematically described a series of antibacterial quinolones by means of molecular topology. We have used molecular descriptors and related them to various pharmacological properties by using multilinear regression (MLR) analysis. The regression functions selected by presenting the best combination of a number of quality and validation metrics allowed for the reliable prediction of clearance (CL), and minimum inhibitory concentration 50 against Enterobacter aerogenes (MIC50Ea) and Proteus mirabilis (MIC50Pm). The obtained results clearly reveal that the combination of molecular topology methods and MLR provides an excellent tool for the prediction of pharmacokinetic properties and microbiological activities in both new and existing compounds with different pharmacological activities.

Traditionally, drug development involved the individual synthesis and biological evaluation of hundreds to thousands of compounds with the intention of highlighting their biological activity, selectivity, and bioavailability, as well as their low toxicity. On average, this process of new drug development involved, in addition to high economic costs, a period of several years before hopefully finding a drug with suitable characteristics to drive its commercialization. Therefore, the chemical synthesis of new compounds became the limiting step in the process of searching for or optimizing leads for new drug development. This need for large chemical libraries led to the birth of high-throughput synthesis methods and combinatorial chemistry. Virtual combinatorial chemistry is based on the same principle as real chemistry—many different compounds can be generated from a few building blocks at once. The difference lies in its speed, as millions of compounds can be produced in a few seconds. On the other hand, many virtual screening methods, such as QSAR (Quantitative Sturcture-Activity Relationship), pharmacophore models, and molecular docking, have been developed to study these libraries. These models allow for the selection of molecules to be synthesized and tested with a high probability of success. The virtual combinatorial chemistry–virtual screening tandem has become a fundamental tool in the process of searching for and developing a drug, as it allows the process to be accelerated with extraordinary economic savings.

Since 2017, the SWICEU team has developed various informative actions and innovative gamification supports to educate and raise awareness about antimicrobial resistance (AMR) and the correct use of antibiotics among the general population especially among young people. This case study presents the results obtained in the last 5 years with the strategies carried out by this team, composed of students and professors of Health Sciences, Industrial Design Engineering, and Communication Sciences at CEU Cardenal Herrera University (CEU UCH) in Valencia (Spain). Over the past 5 years, playful educational supports have been developed to make the health problem of bacterial resistance and the action of antibiotics more understandable among young people. The dissemination media used, with the same objective of teaching and raising awareness about AMR in a creative and innovative way, have been selected according to the trends in digital communication and use of scientific and health content provided by the most recent studies carried out among the Spanish population. These strategies have included decalogues or “tips” with useful advice, infographics, YouTube videos, Twitter threads, online challenges on Kahoot, stories on Instagram, use of QR codes, etc. These actions have also obtained diffusion in the media and have been awarded by different national and international entities. The good results obtained in the case under study allow us to establish recommendations for the design of innovative educational gamification and dissemination supports on AMR, especially aimed at younger audiences.

Antimicrobial resistance (AMR) remains a serious global health problem. Spain is the fifth country in Europe with the highest consumption of antibiotics, due in part to ignorance of the good use of these drugs and the problem of AMR. To avoid a post-antibiotic era, adequate training on this problem is key to create social awareness. This study aimed to evaluate the impact that the SWICEU project, an academic program about antibiotic discovery, has had on the knowledge of AMR and rational use of antimicrobials in preuniversity students from seven schools in the province of Valencia during five academic years (2017–2021), as well as to evaluate the level of satisfaction of university and pre-university students who have participated in the project. For this study, a survey was carried out with multiple-choice questions with a single correct answer to evaluate the knowledge acquired by pre-university students before and after the project. A satisfaction survey was also designed with a Likert scale from the lowest to the highest level of satisfaction for the two groups of students after the project. Data on knowledge surveys indicated an increase in the mean number of correct answers after the sessions. In satisfaction surveys, we highlighted the issue that referred to the project’s recommendation. The data obtained confirm this project as a valuable activity, as it allows learning about AMR and the rational use of antibiotics in a pleasing and attractive way for young pre-university and university students.

The variability of methicillin-resistant Staphylococcus aureus (MRSA), its rapid adaptive response against environmental changes, and its continued acquisition of antibiotic resistance determinants have made it commonplace in hospitals, where it causes the problem of multidrug resistance. In this study, we used molecular topology to develop several discriminant equations capable of classifying compounds according to their anti-MRSA activity. Topological indices were used as structural descriptors and their relationship with anti-MRSA activity was determined by applying linear discriminant analysis (LDA) on a group of quinolones and quinolone-like compounds. Four extra equations were constructed, named DFMRSA1, DFMRSA2, DFMRSA3 and DFMRSA4 (DFMRSA was built in a previous study), all with good statistical parameters, such as Fisher–Snedecor F (>68 in all cases), Wilk’s lambda (<0.13 in all cases), and percentage of correct classification (>94% in all cases), which allows a reliable extrapolation prediction of antibacterial activity in any organic compound. The results obtained clearly reveal the high efficiency of combining molecular topology with LDA for the prediction of anti-MRSA activity.