Exploiting Novel Combined Host- and Pathogen-Directed Therapies for Combating Bacterial Multidrug Resistance

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Background

Infectious diseases represent one of the main causes of morbidity and mortality worldwide. In addition, the frequency and spectrum of antibiotic resistance in specific bacterial pathogens continues to increase worryingly, with particular concerns on Mycobacterium tuberculosis and on several Gram-positive (e.g. Streptococcus pneumoniae, Staphylococcus aureus and enterococci) as well as Gram-negative bacteria (e. g. Klebsiella pneumoniae, Escherichia coli, Enterobacter spp, Acinetobacter baumannii, and Pseudomonas aeruginosa). In recent years, there has been a dearth of new antibiotics in the drug development pipeline, and the emergence of resistance to last resort antibiotics, such as the carbapenems and polymyxins make urgent the need for novel therapeutic approaches which may reduce the global emergence of antimicrobial resistance (AMR). Today, about 700,000 deaths are annually caused by AMR, with a burden of about 10 million deaths per year foreseen by the year 2050, if any adequate countermeasures will not be taken.

Recently, novel anti-infectious therapeutic approaches based on the modulation of host response (Host directed therapy, HDT) have been proposed to counteract the emergence of AMR, with some of them already in clinical practice as repurposed drugs, like azythromycin and erythromycin for their anti-inflammatory properties. Improvement in HDT strategies requires studies focusing on i) how the different pathogens escape immune mechanisms to ensure their survival/dissemination, ii) new mechanisms/players of protective anti-infective immune response and iii) the activation of intracellular molecular pathways for pathogen control. Thus, HDT comprises any drug that can enhance antimicrobial response (ROS generation, autophagy, phagolysosome maturation, antimicrobial peptides) and/or down-modulate tissue-damaging immune response. Autophagy inducers (e.g. metformin), protein kinase inhibitors (e.g. the anti-chronic myeloid leukemia drugs Imatinib, Dasatinib, and Nilotinib) and cathelicidin inducers (e.g. vitamin D) represent model molecules studied to enhance antimicrobial response. Anti-inflammatory drugs in combination with conventional antibiotics, have been proposed to i) prevent dissemination and confine microbial niches, ii) reduce microbial burden and iii) limit tissue damage in infectious immuno-pathologies. A prototypic example is the administration of corticosteroids in combination with conventional antibiotics to treat aggressive forms of Tuberculosis that has been previously reported to reduce the time of sputum conversion, probably due to the improved antibiotic penetration and action into lung lesions.

Therapeutic approaches targeting the pathogen and/or its products can be defined as pathogen directed therapy (PDT). Today, most of the new antibiotics are based on modifications of traditional antibiotic structures, challenging their longevity as therapeutic options. The control of antimicrobial resistance might certainly benefit from the development of novel antibiotic classes, which do not show cross-resistance to currently used antibiotics. However, innovative compounds increasing pathogen vulnerability may also represent an important goal in the battle against AMR. Among the new therapeutic strategies, anti-virulence therapy has emerged as a promising alternative as it targets specific molecules of the pathogen important for its survival/replication in vivo. Finally, phage therapy has also been recently reconsidered as a possible approach for treating infections caused by tenacious pathogens and its combination with antibiotics has been shown to be superior over the use of single agents.

The strategic targeting of host response (HDT) together with the appropriate antimicrobial treatment of the pathogen (PDT) in a rational combination therapy (RCT) may represent an exploitable strategy to reduce the time of antibiotic therapy, limit tissue damage, avoid antibacterial resistance, and lead to successful treatment and resolution of antimicrobial-resistant infections.

This Research Topic focuses on studies that investigate and discuss the proposed use of novel host- and/or pathogen-directed therapeutic approaches, alone or in combination, to control multidrug-resistant infections. We welcome the submission of articles covering, but not limited to, the following topics:

a. Current drugs and novel therapeutic approaches targeting the innate immune system for enhancing microbicidal activity and preventing antibiotic resistance.
b. Current drugs and novel therapeutic approaches targeting innate immune pathways that are perturbed by a pathogen and contribute to hyper-inflammation.
c. Novel antibiotics, antibiotic combination, anti-virulence factors, phage therapy, biotechnological or off-label drugs to treat AMR infections.
d. Novel therapeutic RCT formulations aimed to reduce microbial burden and/or tissue damage.

The following article types will be accepted for submission: Original Research, Perspective, Review, Mini-Review, Clinical Trial, Commentary, Opinion articles, and Case Reports.

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