Molecular Mechanisms of Host-Pathogen Interactions and their Potential for the Discovery of New Drug Targets

Abstract

Vaccines and chemotherapy have undeniably been the discoveries in the field of biomedical research that have exerted the biggest impact on the improvement of public health. Nevertheless, the development of bacterial resistance to antibiotics has co-evolved over time with the discovery of new drugs. This entails the necessity for continuous research on new anti-infectious agents.The current review highlights recent discoveries in the molecular mechanisms of specific host pathogen interactions and their potential for drug discovery. The focus is on facultative and obligate intracellular pathogens (Mycobacterium, Chlamydia and Legionella) and their manipulation of host cells in regard to inhibition of phagosome maturation and cell death. Furthermore, the composition and role of the SecA2 and the ESX-1 secretion pathways in bacterial virulence and manipulation of infected host cells is discussed. The central hypothesis proposed in this review is that the characterization of bacterial proteins and lipids involved in host cell manipulation (modulins) will provide an abundance of new drug targets. One advantage of targeting such bacterial modulins for drug development is that these anti-modulin drugs will not disrupt the beneficial host microflora and therefore have fewer side effects.

Phytocomponent 4-hydroxy-3-methoxycinnamaldehyde ablates T-cell activation by targeting protein kinase C-θ and its downstream pathways

“…Nevertheless, computational tools significantly accelerate the process of target validation, increase treatment possibilities and decrease the rate of drug failure in the final phase of clinical trials. Computational tools well-thought-out with 'omics' data (proteomics, genomics and metabolomics) are attractive tools for searching of likely targets and off-targets for potent small molecules [14][15][16]. In silico studies enabled us not only to identify the target proteins of 4H3MC but also to unravel its suppressive mechanism in T cells.…”

Role of mycobacteria effectors in phagosome maturation blockage and new drug targets discovery

“…Mtb's PknG was thought to act as an important mediator of phagosome maturation inhibition. One piece of evidence is that inactivation of PknG by gene disruption or chemical inhibition resulted in the maturation of the Mtb-phagosome and intracellular killing of the bacteria [Briken, 2008]. The mechanism of cytosolic translocation of PknG and the precise action of PknG on host trafficking machinery is not known.…”

Genetic Variation inMycoplasma genitalium

“…Pharmaceutical drugs often have specific molecular targets in the host cells [19]. Similarly, various antimicrobials also target specific regions of the microbes [20][21][22]. Currently, almost all host-microbe or microbe-drug interactions at the molecular levels may be traced or estimated using precise molecular technologies [17][18][19][20][21][22].…”

“…Similarly, various antimicrobials also target specific regions of the microbes [20][21][22]. Currently, almost all host-microbe or microbe-drug interactions at the molecular levels may be traced or estimated using precise molecular technologies [17][18][19][20][21][22]. Indeed, we can define the presence of uncultivated or poorly-cultivable microbes in the host cells and estimate these host-microbe interactions using molecular technologies, such as polymerase chain reaction [22,23].…”

“…Therefore, the fundamental pathways in bacterial transcription and translation may be targeted by antimicrobial agents [20][21][22]. For example, the specific molecular target site for macrolides is a large subunit of the bacterial ribosome [24], and fluoroquinolones can also bind to the bacterial gyrase and topoisomerase IV, preventing DNA synthesis [25].…”