Current Medicinal Chemistry - Volume 26, Issue 11, 2019

Lipids are ubiquitous molecules, known to play important roles in various cellular processes. Alterations to the lipidome can therefore be used as a read-out of the signs of disease, highlighting the importance to consider lipids as biomarkers in addition of nucleic acid and proteins. Lipids are among the primary structural and functional constituents of biological tissues, especially cell membranes. Along with membrane formation, lipids play also a crucial role in cell signalling, inflammation and energy storage. It was shown recently that lipid metabolism disorders play an important role in carcinogenesis and development. As well, the role of lipids in disease is particularly relevant for bacterial infections, during which several lipid bacterial virulence factors are recognized by the human innate immune response, such as lipopolysaccharide in Gram-negative bacteria, lipoteichoic acid in Gram-positive bacteria, and lipoglycans in mycobacteria. Compared to nucleic acids and proteins, a complete analysis of the lipidome, which is the comprehensive characterization of different lipid families, is usually very challenging due to the heterogeneity of lipid classes and their intrinsic physicoproperties caused by variations in the constituents of each class. Understanding the chemical diversity of lipids is therefore crucial to understanding their biological relevance and, as a consequence, their use as potential biomarkers for non-infectious and infectious diseases. This mini-review exposes the current knowledge and limitations of the use of lipids as biomarkers of the top global killers which are cancer and bacterial infections.

Group A Streptococcus (GAS) infections are responsible for significant morbidity and mortality worldwide. The outlook for an effective global vaccine is reduced because of significant antigenic variation among GAS strains worldwide. Other challenges in GAS therapy include the lack of common access to antibiotics in developing countries, as well as allergy to and treatment failures with penicillin and increasing erythromycin resistance in the industrialized world. At the portal of entry, GAS binds to newly deposited extracellular matrix, which is rich in cellular fibronectin isoforms with extra domain A (EDA, also termed EIIIA) via the surface adhesin, the streptococcal collagen-like protein 1 (Scl1). Recombinant Scl1 constructs, derived from diverse GAS strains, bind the EDA loop segment situated between the C and C’ β-strands. Despite the sequence diversity in Scl1 proteins, multiple sequence alignments and secondary structure predictions of Scl1 variants, as well as crystallography and homology modeling studies, point to a conserved mechanism of Scl1-EDA binding. We propose that targeting this interaction may prevent the progression of infection. A synthetic cyclic peptide, derived from the EDA C-C’ loop, binds to recombinant Scl1 with a micromolar dissociation constant. This review highlights the current concept of EDA binding to Scl1 and provides incentives to exploit this binding to treat GAS infections and wound colonization.

Background: Tuberculosis (TB), one of the leading causes of death worldwide, is difficult to diagnose based only on signs and symptoms. Methods for TB detection are continuously being researched to design novel effective clinical tools for the diagnosis of TB. Objective: This article reviews the methods to diagnose TB at the latent and active stages and to recognize prospective TB diagnostic methods based on nanomaterials. Methods: The current methods for TB diagnosis were reviewed by evaluating their advantages and disadvantages. Furthermore, the trends in TB detection using nanomaterials were discussed regarding their performance capacity for clinical diagnostic applications. Results: Current methods such as microscopy, culture, and tuberculin skin test are still being employed to diagnose TB, however, a highly sensitive point of care tool without false results is still needed. The utilization of nanomaterials to detect the specific TB biomarkers with high sensitivity and specificity can provide a possible strategy to rapidly diagnose TB. Although it is challenging for nanodiagnostic platforms to be assessed in clinical trials, active TB diagnosis using nanomaterials is highly expected to achieve clinical significance for regular application. In addition, aspects and future directions in developing the high-efficiency tools to diagnose active TB using advanced nanomaterials are expounded. Conclusion: This review suggests that nanomaterials have high potential as rapid, costeffective tools to enhance the diagnostic sensitivity and specificity for the accurate diagnosis, treatment, and prevention of TB. Hence, portable nanobiosensors can be alternative effective tests to be exploited globally after clinical trial execution.

Salmonellosis continues to be a significant worldwide health problem. Despite rapid progress in identifying mechanisms of Salmonella virulence and resistance to chemicals, our knowledge of these mechanisms remains limited. Furthermore, it appears that the resistance to antibiotics can be amplified by ubiquitous usage of the disinfectants (biocides), both by industry and by ordinary households. Salmonella, as other Gram-negative bacteria possess outer membrane proteins (OMPs), which participate in maintaining cell integrity, adapting to environment, and interacting with infected host. Moreover, the OMPs may also contribute to resistance to antibacterials. This review summarizes the role of OMPs in Salmonella serum resistance, antibiotics resistance and cross-resistance to biocides. Although collected data do not allow to assign OMPs as markers of the Salmonella susceptibility to the above-mentioned factors, some of these proteins retain a dominant presence in certain types of resistance.

The environment exerts strong influence on microbes. Adaptation of microbes to changing conditions is a dynamic process regulated by complex networks. Pseudomonas aeruginosa is a life-threating, versatile opportunistic and multi drug resistant pathogen that provides a model to investigate adaptation mechanisms to environmental changes. The ability of P. aeruginosa to form biofilms and to modify virulence in response to environmental changes is coordinated by various mechanisms including two-component systems (TCS), and secondary messengers involved in quorum sensing (QS) and c-di-GMP networks (diguanylate cyclase systems, DGC). In this review, we focus on the role of c-di-GMP during biofilm formation. We describe TCS and QS signal cascades regulated by c-di-GMP in response to changes in the external environment. We present a complex signaling network dynamically changing during the transition of P. aeruginosa from the free-living to sessile mode of growth.

Background: Elucidating the mechanisms of recurrence of embryonic signaling pathways in tumorigenesis has led to the discovery of onco-fetal players which have physiological roles during normal development but result aberrantly re-activated in tumors. In this context, Nodal and Cripto-1 are recognized as onco-developmental factors, which are absent in normal tissues but are overexpressed in several solid tumors where they can serve as theranostic agents. Objective: To collect, review and discuss the most relevant papers related to the involvement of Nodal and Cripto-1 in the development, progression, recurrence and metastasis of several tumors where they are over-expressed, with a particular attention to their occurrence on the surface of the corresponding sub-populations of cancer stem cells (CSC). Results: We have gathered, rationalized and discussed the most interesting findings extracted from some 370 papers related to the involvement of Cripto-1 and Nodal in all tumor types where they have been detected. Data demonstrate the clear connection between Nodal and Cripto-1 presence and their multiple oncogenic activities across different tumors. We have also reviewed and highlighted the potential of targeting Nodal, Cripto-1 and the complexes that they form on the surface of tumor cells, especially of CSC, as an innovative approach to detect and suppress tumors with molecules that block one or more mechanisms that they regulate. Conclusion: Overall, Nodal and Cripto-1 represent two innovative and effective biomarkers for developing potential theranostic anti-tumor agents that target normal as well as CSC subpopulations and overcome both pharmacological resistance and tumor relapse.

A major goal in tuberculosis (TB) research is the identification, among the subjects infected with Mycobacterium tuberculosis (Mtb), of those with active TB, or at higher risk of developing active disease, from the latently infected subjects. The classical heterogeneity of Mtb infection and TB disease is a major obstacle toward the identification of reliable biomarkers that can stratify Mtb infected subjects based on disease risk. The heparin-binding haemagglutinin (HBHA) is a mycobacterial surface antigen that is implicated in tuberculosis (TB) pathogenesis. The host immune response against HBHA varies depending on the TB status and several studies are supporting the role of HBHA as a useful biomarker of TB.