Abstract
Novel drugs are needed to treat a variety of persistent diseases caused by intracellular bacterial pathogens. Virulence pathways enable many functions required for the survival of these pathogens, including invasion, nutrient acquisition, and immune evasion. Inhibition of virulence pathways is an established route for drug discovery; however, many challenges remain. Here, we propose the biggest problems that must be solved to advance the field meaningfully. While it is established that we do not yet understand the nature of chemicals capable of permeating into the bacterial cell, this problem is compounded when targeting intracellular bacteria because we are limited to only those chemicals that can permeate through both human and bacterial outer envelopes. Unfortunately, many chemicals that permeate through the outer layers of mammalian cells fail to penetrate the bacterial cytoplasm. Another challenge is the lack of publicly available information on virulence factors. It is virtually impossible to know which virulence factors are clinically relevant and have broad cross-species and cross-strain distribution. In other words, we have yet to identify the best drug targets. Yes, standard genomics databases have much of the information necessary for short-term studies, but the connections with patient outcomes are yet to be established. Without comprehensive data on matters such as these, it is difficult to devise broad-spectrum, effective anti-virulence agents. Furthermore, anti-virulence drug discovery is hindered by the current state of technologies available for experimental investigation. Antimicrobial drug discovery was greatly advanced by the establishment and standardization of broth microdilution assays to measure the effectiveness of antimicrobials. However, the currently available models used for anti-virulence drug discovery are too broad, as they must address varied phenotypes, and too expensive to be generally adopted by many research groups. Therefore, we believe drug discovery against intracellular bacterial pathogens can be advanced significantly by overcoming the above hurdles.
Highlights
Communicable diseases continue to burden the globe [1]
Relevant intracellular bacteria can be seen in Supplementary Table S1
It is well recognized that antimicrobials are hard to find because this has been the major focus of the drug discovery and development community, but the challenges we face in drug discovery against intracellular bacteria have rarely been addressed
Summary
Communicable diseases continue to burden the globe [1]. The cost of infections in terms of lives and financial burden is huge [1,2,3]. A limited selection of antimicrobials (e.g., aminoglycosides, fluoroquinolones, macrolides, rifamycins, tetracyclines) are useful against intracellular pathogens (Supplementary Table S1) This limited armamentarium means that each time an antibiotic succumbs to resistance, our options for appropriate treatment reduce drastically. The powerful advantage of these medications would be that they do not require bacterial cell division for an effect to take place: traditional antimicrobials (i.e., antibiotics) are only useful against bacteria undergoing continuous cell division, such as intracellular bacterial colonies (IBCs). They would not function against a subpopulation of non-dividing bacteria, such as persisters or quiescent cells. It is well recognized that antimicrobials are hard to find because this has been the major focus of the drug discovery and development community, but the challenges we face in drug discovery against intracellular bacteria have rarely been addressed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
