Current Medicinal Chemistry (v.22, #18)

Meet Our Editorial Board Member: by Agapios Sachinidis (2111-2111).

Editorial (Thematic Issue: New Antimicrobial Therapeutics) by Andre Luis Souza dos Santos, Marta Helena Branquinha, Claudia Masini d'Avila-Levy, Lucimar Ferreira Kneipp, Catia Lacerda Sodre (2112-2115).

Current Developments in Antimicrobial Surface Coatings for Biomedical Applications by J.J.T.M. Swartjes, P.K. Sharma, T.G. van Kooten, H.C. van der Mei, M. Mahmoudi, H.J. Busscher, E.T.J. Rochford (2116-2129).
Bacterial adhesion and subsequent biofilm formation on material surfaces represent a serious problem in society from both an economical and health perspective. Surface coating approaches to prevent bacterial adhesion and biofilm formation are of increased importance due to the increasing prevalence of antibiotic resistant bacterial strains. Effective antimicrobial surface coatings can be based on an anti-adhesive principle that prevents bacteria to adhere, or on bactericidal strategies, killing organisms either before or after contact is made with the surface. Many strategies, however, implement a multifunctional approach that incorporates both of these mechanisms. For anti-adhesive strategies, the use of polymer chains, or hydrogels is preferred, although recently a new class of super-hydrophobic surfaces has been described which demonstrate improved anti-adhesive activity. In addition, bacterial killing can be achieved using antimicrobial peptides, antibiotics, chitosan or enzymes directly bound, tethered through spacer-molecules or encased in biodegradable matrices, nanoparticles and quaternary ammonium compounds. Notwithstanding the ubiquitous nature of the problem of microbial colonization of material surfaces, this review focuses on the recent developments in antimicrobial surface coatings with respect to biomaterial implants and devices. In this biomedical arena, to rank the different coating strategies in order of increasing efficacy is impossible, since this depends on the clinical application aimed for and whether expectations are short- or long term. Considering that the era of antibiotics to control infectious biofilms will eventually come to an end, the future for biofilm control on biomaterial implants and devices is likely with surface-associated modifications that are non-antibiotic related.

The possibility to develop new antibacterial agents raised much interest recently. The main classes of antibiotics clinically used nowadays act towards the inhibition of four classical targets: a) cell wall biosynthesis; b) protein biosynthesis; c) DNA and RNA biosynthesis; d) folate biosynthesis. Recently, carbonic anhydrases (CAs, EC started to be investigated in detail in pathogenic bacteria, in the search for antibiotics with a novel mechanism of action, since it has been demonstrated that in many bacteria, CAs are essential for the life cycle of the organism and that their inhibition leads to growth impairment or growth defects of the pathogen. CAs catalyze a simple but physiologically relevant reaction in all life kingdoms, carbon dioxide hydration to bicarbonate and protons. Several classes of CA inhibitors (CAIs) are known to date: the metal complexing anions and the unsubstituted sulfonamides, 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, generating trigonal– bipyramidal species are the classical, most frequently investigated ones. In many cases effective inhibitors were detected, some of which also inhibited the bacterial growth in vivo. However, very few of the detected inhibitors were also selective for the bacterial over the human, off target isoforms such as hCA II. Using structure-based drug design processes, we estimate that it will be possible to achieve the desired selectivity for inhibiting preferentially the bacterial but not the host CA isoforms.

With the alarming resistance to currently used antibiotics, there is a serious worldwide threat to public health. Therefore, there is an urgent need to search for new antibiotics or new cellular targets which are essential for survival of the pathogens. However, during the past 50 years, only two new classes of antibiotics (oxazolidinone and lipopeptides) have reached the clinic. This suggests that the success rate in discovering new/novel antibiotics using conventional approaches is limited and that we must reconsider our antibiotic discovery approaches. While many new strategies are being pursued lately, this review primarily focuses only on a few of these novel/new approaches for antibiotic discovery. These include structure-based drug design (SBDD), the genomic approach, anti-virulence strategy, targeting nonmultiplying bacteria and the use of bacteriophages. In general, recent advancements in nuclear magnetic resonance, Xcrystallography, and genomic evolution have significant impact on antibacterial drug research. This review therefore aims to discuss recent strategies in searching new antibacterial agents making use of these technical novelties, their advantages, disadvantages and limitations.

Antimicrobial Photosensitizers: Drug Discovery Under the Spotlight by Rui Yin, Michael R. Hamblin (2159-2185).
Although photodynamic therapy (PDT) was discovered over a hundred years ago by its ability to destroy microorganisms, it has been developed mainly as a cancer therapy. In recent years, due to the inexorable rise in multi-antibiotic resistant strains of pathogens, PDT is being considered as a versatile antimicrobial approach to which microbial cells will not be able to develop resistance. The goal of this review is to survey the different classes of chemical compounds that have been tested as antimicrobial photosensitizers. Some of these compounds have been known for many years, while others have been rationally designed based on recently discovered structural principles. Tetrapyrrole-based compounds (some of which are approved as cancer therapies) that efficiently generate singlet oxygen are more efficient and broad-spectrum when they bear cationic charges, As the macrocycle structure moves from porphyrins to chlorins to phthalocyanines to bacteriochlorins the long wavelength absorption moves to the near-infrared where tissue penetration is better. Four main types of natural products have been tested: curcumin, riboflavin, hypericin and psoralens. Phenothiazinium dyes, such as methylene blue and toluidine blue, have been tested, and some are clinically approved. A variety of non-phenothiazinium dyes with xanthene, triarylmethane and indocyanine structures have also been tested. New ring structures based on BODIPY, squaraine and fullerene cages can also mediate antimicrobial PDT. Finally the process of photocatalysis using titanium dioxide can also have medical uses. Designing new antimicrobial photosensitizers is likely to keep chemists engaged for a long time to come.

Sterol Biosynthesis Pathway as an Alternative for the Anti-Protozoan Parasite Chemotherapy by Sara Teixeira de Macedo-Silva, Wanderley de Souza, Juliany C. Fernandes Rodrigues (2186-2198).
Sterols play an essential role in the physiology of eukaryotic cells; they play a pivotal role in the normal structure and function of cell membranes and also act as precursors for the synthesis of several different molecules like steroid hormones. Trypanosomatids and fungi have an essential requirement of ergosterol and other 24-alkyl sterols, which are absent in mammalian cells, for their survival and growth. At least 20 metabolic steps are necessary to synthesize sterols as cholesterol and ergosterol with the involvement of different specific enzymes. Some enzymes have been studied in detail in order to find new inhibitors that are able to abolish the parasite growth in vitro; besides, they also promote the curative efficacy in murine models of infection, thus opening new possibilities to introduce new drugs for the treatment of leishmaniasis and Chagas' disease. Sterols biosynthesis inhibitors (SBIs) can potentially be used as a chemotherapeutic agent against trypanosomatids. Actually, there are several drugs that interfere with the SB pathway, and some of them are already in clinical trials, such as posaconazole, and a new pro-drug, the ravuconazole. Furthermore, new approaches are being used, such as the combination of drugs, to reduce the resistance and minimize toxic effects. In this review, we discuss the main steps of the SB pathway, showing each enzyme involved in the steps, as well as the antiproliferative, physiological, biochemical, and ultrastructural effects of the several known inhibitors.

Tuberculosis: An Inorganic Medicinal Chemistry Perspective by Livia Viganor, Ciaran Skerry, Malachy McCann, Michael Devereux (2199-2224).
Tuberculosis (TB) which is caused by the resilient pathogen Mycobacterium tuberculosis (MTB) has re-emerged to become a leading public health problem in the world. The growing number of multi-drug resistant MTB strains and the more recently emerging problem with the extensively drug resistant strains of the pathogen are greatly undermining conventional anti-TB therapeutic strategies which are lengthy and expose patients to toxicity and other unwanted side effects. The search for new anti-TB drugs essentially involves either the repurposing of existing organic drugs which are now off patent and already FDA approved, the synthesis of modified analogues of existing organic drugs, with the aim of shortening and improving drug treatment for the disease, or the search for novel structures that offer the possibility of new mechanisms of action against the mycobacterium. Inorganic medicinal chemistry offers an alternative to organic drugs through opportunities for the design of therapeutics that target different biochemical pathways. The incorporation of metal ions into the molecular structure of a potential drug offers the medicinal chemist an opportunity to exploit structural diversity, have access to various oxidation states of the metal and also offer the possibility of enhancing the activity of an established organic drug through its coordination to the metal centre. In this review, we summarize what is currently known about the antitubercular capability of metal complexes, their mechanisms of action and speculate on their potential applications in the clinic.

Cruzipain: An Update on its Potential as Chemotherapy Target against the Human Pathogen Trypanosoma cruzi by M.H. Branquinha, S.S.C. Oliveira, L.S. Sangenito, C.L. Sodre, L.F. Kneipp, C.M. d'Avila-Levy, A.L.S. Santos (2225-2235).
Chagas' disease is one of the most impactful and prevalent neglected tropical diseases in the Americas, specially affecting the poor and underdeveloped areas in Latin America. Aggravating this scenario, the medicines used in the current chemotherapy are old, toxic and present a low efficacy to treat the chronic stage of this disease. In addition, resistant strains of Trypanosoma cruzi, the etiological agent, are frequently reported. So, there is an imperative requirement for novel chemotherapeutic options to treat this debilitating disease. In this context, peptidases have emerged as potential targets and, consequently, proteolytic inhibitors have confirmed to be valuable drugs against several human pathologies. In this line of thinking, T. cruzi produces a major multifunctional cysteine peptidase, named cruzipain, which directly and/or indirectly orchestrates several physiological and pathological processes, which culminate in a successful parasitic infection. Taken together, these findings point out that cruzipain is one of the most important targets for driving a chemotherapy approach against the human pathogen T. cruzi. The present review summarizes some of the recent advances and failures in this area, with particular emphasis on recently published studies.