Current Topics in Medicinal Chemistry - Volume 17, Issue 11, 2017

Background: Clinically used antibiotics act through one of these four mechanisms: cell wall biosynthesis inhibition, inhibition of protein biosynthesis, interference with DNA and RNA synthesis and the folate pathway. Objective: The metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) widespread in microorganisms and present as three genetically distinct families may be considered for the design of antiinfective agents with a different mechanism of action compared to the clinically used antibiotics. CAs are crucial for the life cycle of the pathogen, interfering with pH regulation and biosynthetic processes in which CO2 or bicarbonate are substrates. CA inhibition was shown to lead to debilitation or growth defects of several pathogenic bacteria. Method: CAs catalyzes the interconversion between carbon dioxide to bicarbonate, leading to the formation of protons, and thus affecting pH homeostasis. Several classes of CA inhibitors (CAIs) are known to date, among which the metal complexing anions, the unsubstituted sulfonamides, the dithiocarbamates, etc., which bind to the Zn(II) ion of the enzyme either by substituting the non-protein zinc ligand or add to the metal coordination sphere. Results: Effective inhibitors for many bacterial CAs belonging to the α-, β-, and γ-CA classes were detected, some of which inhibited bacterial growth in vivo. Few of the inhibitors investigated so far were also selective for the bacterial over the human CA isoforms, which may pose problems for their wide clinical applications. Conclusion: Structure-based drug design campaigns might lead to the achievement of the desired selectivity/ potency for preferentially inhibiting bacterial but not the host CAs.

Trichomoniasis is a sexually transmitted disease (STD) caused by infection with the protozoan parasite Trichomonas vaginalis. It is considered the most prevalent non-viral sexually transmitted disease worldwide. Recently, the infection has been associated with adverse outcomes of pregnancy and increased risks of HIV acquisition and transmission, as well as an association with cervical and prostate cancers. The consequences of trichomoniasis are likely much greater than previously recognized, both at the individual and the community level. Since many cases are asymptomatic, and the most common approach used for diagnosis (wet mount) is also one of the least sensitive, millions of T. vaginalis infections remain undiagnosed and therefore untreated. The purpose of this review is to address what is known about the treatment of T. vaginalis infections and what additional approaches could be pursued. The increasing recognition of the potential public health implications of trichomoniasis has resulted in greater attention to improving effectiveness of the interventions for affected individuals. Currently, treatment relies almost solely on one class of drugs, the 5- nitroimidazoles, which causes concern should widespread drug resistance arise. There are also concerns regarding which 5-nitroimidazole to use as not all of them are active against T. vaginalis. Finally, new therapeutic targets and active compounds with treatment potential are considered.

Antibiotic resistance is one of the biggest public concerns in the 21st century. Host-defense peptides (HDPs) can potentially mitigate the problem through bacterial membrane disruption; however, they suffer from moderate activity and low stability. We recently developed a new class of peptidomimetics termed “AApeptides”. This class of peptidomimetics can mimic the mechanism of action of HDPs, and effectively arrest the growth of multidrug resistant Gram-positive and Gram-negative bacteria. As they are built on unnatural backbone, they are resistant to proteolytic degradation. In this review, we summarize the development of this class of antimicrobial peptidomimetics, and discuss the future perspective on how they can move forward on combating antibiotic resistance.

The “antibiotic era”, characterized by the overuse and misuse of antibiotics, over the last half-century has culminated in the present critical “era of resistance”. The treatment of bacterial infections is challenging because of a decline in the current arsenal of useful antibiotics and the slow rate of new drug development. The discovery of a new gene (mcr-1) in 2015, which enables bacteria to be highly resistant to polymyxins (such as colistin), the last line of antibiotic defence left, heralds a new level of concern as this gene is susceptible to horizontal gene transfer, with alarming potential to be spread between different bacterial populations, suggesting that the progression from “extensive drug resistance” to “pan-drug resistance” may be inevitable. Clearly there is a need for the development of novel classes of anti-bacterial agents capable of killing bacteria through mechanisms that are different to those of the known classes of antibiotics. 1,10-phenanthroline (phen) is a heterocyclic organic compound which exerts in vitro antimicrobial activity against a broad-spectrum of bacteria. The antimicrobial activity of phen can be significantly modulated by modifying its structure. The development of metal-phen complexes offers the medicinal chemist an opportunity to expand such structural diversity by controlling the geometry and varying the oxidation states of the metal centre, with the inclusion of appropriate auxiliary ligands in the structure, offering the opportunity to target different biochemical pathways in bacteria. In this review, we summarize what is currently known about the antibacterial capability of metal-phen complexes and their mechanisms of action.

The introduction of the HIV aspartic peptidase inhibitors (HIV-PIs) has revolutionized the medical arena, since they have drastically reduced the number and the severity of opportunistic infections, including the protozoal diseases that afflict the HIV-infected individuals worldwide. HIV-PIs rapidly and profoundly diminish the viral load, which is paralleled by increase in the CD4+ T lymphocyte counts and stimulation of the survival and activation of neutrophil, monocyte and endothelial cells, culminating in a vigorous reduction in the number of deaths due to the AIDS, in the number of new cases of AIDS and in the number of hospitalization days. Many research groups around the globe are trying to decipher both the in vitro and in vivo antiprotozoal mechanisms behind the use of HIVPIs. These studies have been supported by the urgent need to discover novel active compounds able to treat incurable parasitoses, including three major neglected diseases: malaria, leishmaniasis and Chagas’ disease. The present review summarizes the recent advances on the effects of HIV-PIs against Plasmodium spp., Leishmania spp. and Trypanosoma cruzi.