Anti-Infective Agents - Volume 17, Issue 2, 2019

The ever-increasing threat of bacterial infections and antimicrobial resistance calls for a global effort to deal with this problem. This fast and universal dissemination of antimicrobialresistant bacterial strains resulted in the diminution of therapeutic alternatives for various infectious diseases. Besides, the unaffordability of efficacious antimicrobials coupled with the occurrence of unpleasant adverse effects calls for the exploration of alternative agents with possible antibacterial effect. All these challenges of microbes have posed new drives to the scientific communities. Researchers are now assessing the possible alternative antimicrobial agents for fighting bacterial infections and antimicrobial resistance. Therefore, this review emphasizes on the role of nonsteroidal anti-inflammatory agents as potential sources of novel antibacterial agents on which preliminary studies and randomized controlled trials had been performed. The review also deals with the possible antibacterial mechanism of actions and the likely effects of non-steroidal antiinflammatory drugs when combined along with conventional antibacterial agents.

Introduction: Staph infection, caused by a bacterium known as Staphylococcus aureus, results in a range of diseases from cellulitis to meningitis. Dicoumarol compounds are now emerging as new anti-Staph infection agents as they possess a different chemical structure than compounds used in previous treatments, in order to combat antibiotic-resistant strains. However, it is unclear how such chemical modulations to the dicoumarol backbone structure achieve higher drug performance. Methods: The following review analyzed various quantitative structure-activity relationship (QSAR) studies on dicoumarol compounds and compared them against the corresponding minimum inhibitory concentration and binding affinity values. Results: Compared to the antimicrobial activity, the dicoumarol derivatives with electron withdrawing substituents, CL, NO2, and CF3 showed an inverse correlation; whereas, the opposite was observed with electron donating compounds such as OH, OMe, and amine groups. Based on the interactions of dicoumarol at the active site, an “aromatic donor-acceptor” relationship was proposed as the method of action for this drug. Furthermore, substituent positioning on the benzene ring was found to exert a greater effect on the binding affinity, speculating that the mechanism of action is two characteristics based, needing, both, the proper aromatic pi-pi interaction for stabilization and direct binding to the OH group in the Tyrosine residue, affected by the steric hindrance. Conclusion: This foundational review can enhance productivity sought by the pharmaceutical agency to use combinational chemistry to increase the efficiency to discover new hits in the synthesis of dicoumarol drugs against Staph infection.

Background: The conjugates of antibiotics are new molecules that might show new antibacterial spectrum and overcome resistance of insusceptible bacterial strains. Modification of known antibiotics like Clarithromycin with active fragments is laborious and proven method to overcome resistance of such strains. Methods: The conjugates of Clarithromycin and Benzo[c][1,2]oxaboroles were synthesized using long linkers to extend antimicrobial spectrum of this antibiotic. Results and Discussion: Unexpected intramolecular deboronation of these bioconjugated was found to occur when the linker contained two or more CH2-groups. Molecular modeling was used to understand the source of instability and show a possibility of intramolecular complex of carbonyl group at C-9 in Clarithromycin core and hydroxy-borole moiety. This could facilitate nucleophilic attack of methanol used in reactions to destroy benzo[c][1,2]oxaboroles fragments and leave stable hydroxyl-aryl molecules. Conclusion: The loss of boron from benzo[c][1,2]oxoborole fragments leads to the significant decrease of antimicrobial activity of synthesized antibiotics.

Background: A series of novel 3-(1,3-dioxoisoindolin-2-yl)-N-substituted phenyl benzamide derivatives was synthesized and tested in vitro against human immunodeficiency virus type-1 Integrase (HIV-1 IN). Methods: Out of the 18 analogues, six (compounds 16c, 16h, 16i, 16m, 16n and 16r) showed significant inhibition of strand transfer by HIV-1 integrase. For these six compounds. IC50 was below 5.0 μM. In silico docking studies revealed that the presence of 2-phenyl isoindoline-1,3-dione motif was essential as it was found to interact with active site magnesium. Results: To further confirm the results, cell-based HIV-1 and HIV-2 inhibitory assay was carried out. Conclusion: These compounds possess structural features not seen in previously reported HIV-1 integrase inhibitors and thus can help further optimization of anti-HIV-1 integrase activity.

Background: Multiple antibiotic resistant bacteria represent a challenge in the treatment of infections. It is imperative, therefore, that new substances with antimicrobial properties should be searched to fight these microorganisms. Objective: A series of 5-benzylidene-2, 4-dioxothiazolidin-3-yl benzoic acid derivatives were synthesized and evaluated their antimicrobial potential. The compounds were synthesized by both conventional and microwave synthesizers. Methods: In this study, a series of 5-benzylidene-2, 4-dioxothiazolidin-3-yl benzoic acid derivatives were synthesized by Knoevenagel condensation of 2, 4-thiazolidinedione with substituted aryl aldehydes followed by substitution of 3-amino group with p-chlorobenzoic acid. All the synthesized compounds were characterized by spectral (FT-IR, mass and 1HNMR) and elemental analysis. The compounds were evaluated for their in-vitro antimicrobial activities against Gram-positive bacteria, Gram-negative bacteria and a fungal strain by agar well diffusion assay method and solid dilution method. Results: The compounds exhibited appreciable antimicrobial activity. Compound 4-(5-(2- chlorobenzylidene)-2, 4-dioxothiazolidin-3-yl)benzoic acid (3f) expressed potent antimicrobial activities against all of the microbial strains examined in this study with MIC values ranging between 0.6-0.8 μg/mL and diameter of the zone of inhibition between 17.2-19.5 mm at the concentration of 200 μg/mL. Conclusion: There was a marked decrease in the reaction time, under mild conditions through microwave synthesis wherein it presented a green approach towards syntheses of the thiazolidinedione derivatives. All compounds exhibited mild to moderate antimicrobial activity. The results of tested bioactive assay showed that the nature of the substituent on the phenyl ring significantly influenced the antimicrobial activity. Among the chloro, bromo and methoxy substituted derivatives, chloro derivative possessed the highest activity followed by bromo and then methoxy. The position of the substituents on the arylidene nucleus also affected the activity and it was found that generally ortho-substituted derivatives showed better antimicrobial activity than others.

Background: As natural herbs and medicinal plants extracts are widely used as alternative treatments for different parasitic diseases, some have been tested on Cryptosporidium either in vitro or in vivo. This study assessed the prophylactic and therapeutic treatments' effect of Moringa oleifera (M. oleifera) leaves methanol extract on immunosuppressed-Cryptosporidium infected mice. Methods: The evaluation was carried out by Cryptosporidium oocysts count in fecal samples, histopathological changes in the intestinal tissues, determination of IFN-γ level in mice sera and measuring the antioxidant activity in the intestinal tissues. Results: Prophylactic treatment by M. oleifera extract lowered Cryptosporidium oocysts shedding from immunosuppressed-infected mice although there was no complete elimination of the parasite. However, therapeutic treatment induced a significant reduction in Cryptosporidium oocysts counts by 91.8% higher than that of the drug control (nitazoxanide) group (77.2%). Histopathologically, the intestinal tissues from immunosuppressed-Cryptosporidium infected mice showed loss of brush border with severe villous atrophy and extensive necrosis. M. oleifera prophylactic treatment induced a moderate improvement of the pathological changes. However, the villi in M. oleifera therapeutic treated mice retained their normal appearance with minimal inflammatory cells. It was observed that M. oleifera extract induced a significant upregulation of IFN-γ in both prophylactic and therapeutic treated groups compared to that of the infected untreated group. In addition, M. oleifera leaves extract exhibited a significant antioxidant activity by reducing the levels of Nitric Oxide (NO) and Malondialdehyde (MDA) and increasing Superoxide Dismutase (SOD) level in the intestinal tissues compared to those of the infected and drug controls. Conclusion: M. oleifera leaves extract has potent prophylactic and therapeutic activities against infection with Cryptosporidium.

Background: American trypanosomiasis, also known as Chagas disease, is caused by the protozoan Trypanosoma cruzi (T. cruzi) and affects approximately 10 to 12 million, primarily in Latin America. Since its discovery in 1909, there is no effective treatment for its chronic phase, with benzonidazole being the only anti-trypanosoma drug used in Brazil, despite the absence of conclusive evidence to prove its efficacy and safety. Thus, it is necessary to develop new drugs that are more effective and selective against Trypanosoma cruzi. Methods: The T. cruzi enzyme Trypanothione Reductase (TcTR) is a validated target for the discovery of new antiprotozoal compounds and we employed the Virtual Screening technique on the database of Nucleus of Bioassays, Biosynthesis and Ecophysiology (NuBBE), aiming to search for new chemical moieties against T. cruzi. From these we selected the 10 best ligand energies interactions and verified their interaction profile with the main TcTR sites through the AuPosSOM server (https://www.biomedicale.univ-paris5.fr/aupossom). Results and Conclusion: Finally, we analyzed some pharmacokinetics and toxicological information through the servers Aggregator Advisor (http://advisor.bkslab.org), Pred-hERG 4.0 (http://labmol.com.br/predherg) and pkCSM (http://biosig.unimelb.edu.au/pkcsm/prediction) which we expect will be useful in in vitro preclinical trials.

Background: In view of the global threat of antimicrobial resistance, novel alternative approaches to deal with infectious bacteria are warranted, in addition to the conventional invasive therapeutic approaches. Objective: This study aimed at investigating whether exposure to sonic stimulation or microwave radiation can affect virulence of pathogenic bacteria toward the model nematode host Caenorhabditis elegans. Methods: Caenorhabditis elegans worms infected with different pathogenic bacteria were subjected to sonic treatment to investigate whether such sound treatment can exert any therapeutic effect on the infected worms. Virulence of microwave exposed bacteria was also assessed using this nematode host. Results: Sound corresponding to 400 Hz, and the divine sound ‘Om’ conferred protective effect on C. elegans in face of bacterial infection, particularly that caused by Serratia marcescens or Staphylococcus aureus. The observed effect seemed to occur due to influence of sound on bacteria, and not on the worm. Additionally, effect of microwave exposure on bacterial virulence was also investigated, wherein microwave exposure could reduce virulence of S. aureus towards C. elegans. Conclusion: Sonic stimulation/ microwave exposure was demonstrated to be capable of modulating bacterial virulence.