Frontiers in Anti-infective Agents

Anti-infective agents are secondary metabolites produced and obtained from a different sources (plants, bacteria, virus, fungi, and marine oceans) with antibacterial or antiviral properties. The mechanism of action of these compounds is also broad and extensive as well. Anti-infective agents (antibacterial or antiviral) possess either a bactericidal/virucidal or bacteriostatic /virustatic ability against microbes and viruses. To impact as safer alternatives for the treatment of emergent and reemergent infectious diseases, it is neccesary to have a better knowledge of the more recent advances in phytomedicine, etnopharmacology, and omics technologies that might lead to therapies a based on natural formulations of adjuvants and/or of different combinations of compounds (e.g. secondary metabolites+antimicrobial peptides) with complementary properties (immunological, pharmacological), that are a promised strategy to curb multidrug resistance strains (MDR) and/or super drug resistance bacteria (XDR). Therefore, the aim of the present chapter is to outline the world of anti- infective agents, along with their mechanism of action.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. TB is one of the top ten causes of death in the world and it is highly prevalent, characterized by the constant occurrence of drug-resistant cases, and confounded by the incidence of respiratory diseases caused by nontuberculous mycobacteria (NTM). The anti-TB drugs commonly used are insufficient and have multiple adverse effects. Therefore, a new strategy to eradicate this infectious disease is required. The implementation of new anti-TB drugs together with host-directed therapy (HDT) can decrease the duration of treatment and improve the TB patients’ health. It is proposed that natural products are an enormous source of bioactive compounds to treat TB. They can be new anti-TB drugs or agents for HDT.

The primary function of antimicrobial molecules is the interaction with pathogens to clear infections. In this chapter, we discuss the role that antimicrobial peptides (AMPs), nitric oxide (NO), and reactive oxygen species (ROS) play in the elimination of intracellular bacteria and their induction by immunomodulators like vitamin D, focusing on the mycobacterial infection. AMPs are the major mechanisms to directly eliminate intracellular bacteria such as Mycobacterium tuberculosis or Salmonella sp. Cathelicidins (LL-37) and β-defensins (HBD-2) are the most studied AMPs, due to their relevance in the immunopathogenesis of several infectious diseases. Additionally, the production of ROS also kills intracellular bacteria directly, especially within the phagosome; patients with ROS deficiencies are susceptible to tuberculous mycobacterial infections. However, excessive production of ROS might induce cell death by apoptosis. The active form of vitamin D (1α,25(OH)2D3) is a key inducer of antimicrobial mechanisms. Vitamin D is involved in redox homeostasis, regulating the effect of ROS and NO to protect the cell integrity; and as an activator of anti-infective pathways for pathogen elimination through induction of AMPs and autophagy. The ability of induction of antimicrobial mechanisms confers these molecules a potential use as adjunct therapies in several infections.

Tuberculosis (TB) is an infectious disease that represents a health problem in the world, with pulmonary tuberculosis (TBP) as the most frequent type of TB. This disease is caused by Mycobacterium tuberculosis (M. tuberculosis) that enters the host by inhalation. M. tuberculosis comes into contact with physiological barriers found in the upper respiratory tract (URT) and with innate immunity through airway epithelial cells (AECs). AECs are endowed with innate receptors (TLRs, NOD1, NOD2, NLRP3, TNFR, EGFR, and C-type lectins) that allow them to interact with microorganisms, or their components, and are a source of antimicrobial peptides (AMPs), such as α- defensins, β-defensins, cathelicidin (LL-37/hCAP-18), pro-inflammatory cytokines and chemokines. However, M. tuberculosis can resist and surpass innate defense mechanisms, descend to the lower respiratory tract (LRT) and arrives at the alveoli. At this site, M. tuberculosis comes into contact with alveolar macrophages (AMs), dendritic cells (DCs), type II epithelial cells, and neutrophils. M. tuberculosis interacts with AMs through TLRs (TLR2, TLR4, and TLR9) and triggers the production of proinflammatory (IL-1β, IL-6, TNF-α, IL-12) and anti-inflammatory cytokines (IL-4, IL- 10). Innate immunity includes phagocytosis, killing, cytokines, and chemokines production with the participation of T cells, later, that orchestrate the elimination of mycobacteria. For M. tuberculosis clearance, it is fundamental that AMs or DCs present mycobacterial antigens to T cells and begin an acquired immune response for mycobacterial elimination. During the infection in the alveolar space, there are innate molecules such as AMPs, ROS, NO, pro-inflammatory cytokines (IL-1β, IL-6, IL-12, IL-18, TNF-α and IFN-γ), anti-inflammatory cytokines (IL-4, IL-10 and TGF-β), and immune specific T cells for M. tuberculosis clearance. Control of TB infection has been associated with IFN-γ production by T cells since it triggers and increases bactericidal AMs activity. However, the alveolar immune response against M. tuberculosis may not be effective due to the evasive mechanisms employed by the mycobacteria and the secretion of its virulent factors.

Autophagy is a lysosome-based degradation pathway of cytosolic cargos activated to prolong survival during starvation and diverse stress conditions by recycling of cellular content. In selective macroautophagy, specific cargos that could be misfolded proteins, damaged organelles, or intracellular pathogens selectively undergo degradation within autolysosomal compartments. However, some pathogens exhibit highly evolved tactics for evading autophagic recognition and are capable of surviving and replicating within the cytoplasm. Because autophagy is inducible in cells infected with pathogens that block autophagy, this mechanism has been proposed to be useful for therapy. In this chapter, we focus on Mycobacterium tuberculosis, one of the top causes of death worldwide and an archetype of intracellular pathogens, and its interaction with the autophagy machinery. First, we describe the generalities of the autophagic process and give examples of the bacterial strategies to evade or exploit autophagy. Also, we discuss the induction of autophagy as a therapeutic approach to circumvent the escape of bacteria from autophagy by using three types of autophagy inducers, the natural compounds, the microbial compound, and drugs. Also, we argue the main concerns that should be taken into account when using autophagy inducers as therapeutic agents.

In recent years, it has been well documented in several studies that there is a close relationship among three of the most important homeostatic-control axes, the nervous, endocrine, and immunologic systems. Clinical and experimental evidence around the world indicates that this physiological phenomenon could be explained as neuro-immune-endocrine interactions (NIEI). The communication between those systems maintains the homeostasis in the presence of stressing stimuli like pathogens (virus, bacteria, fungus, and parasites). Commonly these kinds of stressors generate inflammation processes inside and outside the tissue. Once a pathogen gets into the body, it activates a sensor system through the activation of the innate immune cells such as macrophages and epithelial cells. These cells release cytokines and inflammatory mediators to the circulation such as interleukin-6 (IL-6) and Tumor necrosis factor-alpha (TNF-α), interacting with their specific receptors in different types of cells (local and peripheral cells). In the nervous system, principally in the peripheral nervous system (PNS), there are cytokine receptors to these cytokines, capable to send information from the periphery to the central nervous system (CNS), which is the main control center of the homeostasis. The CNS integrates the information in specific anatomical regions in the brain stem (e.g., a nucleus of the tractus solitarius; NTS) activating hypothalamic cells, which in turn synthesize and secrete hormones to induce more hormones secretion from the pituitary gland and release them into the bloodstream. Some of these hormones travel to stimulate the synthesis and release of anti-inflammatory mediators such as the glucocorticoids, whereas other hormones produce a direct regulatory effect on the immune system through the interaction with its receptor, suppressing or stimulating the immune cells accordingly to the hormones concentration, receptor expression and other molecular, cellular and micro-environmental factors involved. In this chapter, we will review some of the principal molecular and cellular mediators involved in the homeostasis control by the NIE system during the infection with some kind of pathogens.

Helicobacter pylori is a Gram-negative spiral bacteria that has been associated with peptic ulcers, gastritis, duodenitis and it is believed to be the causative agent of gastric cancer and anemia. Its iron requirements when it infects its human host are high, therefore this bacterium has developed mechanisms to obtain iron from human sources. This human pathogen can grow in broth media using as iron source human proteins such as lactoferrin (Lf), haem and haemoglobin (Hb). However, it is still not fully understood how the process of iron acquisition occurs. An in silico analysis has shown that H. pylori has a family of three outer membrane proteins regulated by iron termed FrpB (Iron-regulated outer membrane protein). Two of them: FrpB1 and FrpB2 bind haem and FrpB1 also binds Hb. The last protein, FrpB3 has the capacity of haem-binding. The analysis by 3D model showed that three proteins are structurally conserved with the typical barrel structure inserted into the membrane. Moreover, the necessary motifs for Hb-binding have been identified. Each gene is regulated by the presence of an iron source, for instance FrpB1 is overexpressed if haem is present, while FrpB2 was induced in the presence of haem and Hb. In the case of FrpB3, it is overexpressed in the presence of free iron. It is believed that there are other proteins implicated in iron acquisition that have not been investigated yet. In summary, H. pylori secretes proteins to support the extreme environment present in the stomach. Perhaps iron helps the bacterium to resist the acidic environment of the human stomach and this mechanism is vital for H. pylori during the infection process.

Babesia bovis and Babesia bigemina are protozoan parasites of the Apicomplexa phylum that cause bovine babesiosis, a cattle disease transmitted by ticks of the Rhipicephalus genera. It is a disease of the tropical and subtropical regions, therefore in Mexico, it is present in 51.5% of the national territory. The severe negative impact of cattle ticks and bovine babesiosis on the livestock industry in Mexico and the world persists due to the absence of safe and effective commercial vaccines. Vaccines based on genomics and biotechnological tools promise to be a solution to this problem. With the complete genome sequence of Babesia bovis and Babesia bigemina, genomic studies of these pathogens are now possible and valuable information is available on the essential characteristics of their composition and their comparison with the other Apicomplexa protozoa of importance in human and animal health, as well as the identification of new genes with vaccination or therapeutic potential. In this chapter, we review the latest knowledge in the cellular and molecular mechanisms that trigger a protective, immune response and the identification of the molecular targets for vaccine development, all of which are a key priority to develop control measures against these pathogens.