Expert Commentary & Five-year View
The expansion of knowledge in microbiology and immunology, and the development of powerful weapons (vaccines and antibacterials) had raised the hope of eradicating infectious diseases. However, the microorganisms have succeeded their come back by generating resistance mechanisms, exchanging data and solutions, and finding a new hunting ground in immunocompromised individuals, whose numbers are growing fast, parallel to medical progresses. New viruses and bacteria continue to be discovered and old diseases (gastric ulcer, Whipple's disease) are now classified as infectious diseases. A major concern is the emergence of resistant and multidrug-resistant, pathogens and a significant decline in the production of new antibacterial agents. The '10' × '20' initiative, supported by the Infectious Diseases Society of America, has been created to develop ten new, safe and effective antibiotics by 2020. Pleuromutilins are the latest class of antibiotics launched on the market. New approaches utilize compounds that overcome resistance to common antibacterial phage therapy, bacteriocins, biotherapy with protozoa, or maggot therapy. In the 'third era of antimicrobial treatment', immunomodulators are in the limelight. Many immunomodulating drugs are now on the market and are given in combination with antimicrobial agents.
Whether antimicrobial agents can, by themselves, interfere with the host system has been frequently addressed, mainly with regards to antibacterial agents.
Therapeutic applications of the immunomodulatory properties of various antibacterial drugs are widely acknowledged. For instance, dapsone and clofazimine have been used in various inflammatory and autoimmune dermatoses, and sulfasalazine in spondyloarthritis and Crohn's disease. More recently, the therapeutic benefit of erythromycin A-derived macrolides has been demonstrated in patients with respiratory diseases associated with chronic inflammation (in particular diffuse panbronchiolitis and CF) and in inflammatory skin diseases. Future developments concern ansamycins, cyclines and aminoglycosides.
Ansamycin antibiotics such as geldanamycins (benzoquinone, ansamycins), bind to the N-terminal ATP/ADP binding pocket of HSP90, which leads to the degradation of a range of HSP90 clients proteins, cell cycle arrest and apoptotic cell death. The derivative 17-allylaminogeldanamycin has been the first HSP90 inhibitor to enter clinical trials in patients with advanced solid malignancies and open the way to new compounds in this class.[142] The antibiotic novobiocin has also been shown to interfere with HSP90 and is proposed as an alternative.[143]
Cyclines are an antibiotic class of growing interest. Therapeutic targets of cyclines include skin diseases, rheumatoid arthritis and early diffuse scleroderma, and chronic inflammatory airway diseases (asthma, bronchiectasis, acute respiratory distress syndrome and CF). Animal models and in vitro studies suggest future applications in diabetic nephropathy, ophthalmic diseases (diabetic retinopathy, cataract and so on), allergy, neuroprotective activity and adjunct to antipsychotic medication in patients with schizophrenia.
The aminoglycosides are on the way to 'renaissance'.[144] The possibility of curing genetic diseases (e.g., some CF) by targeting nonsense mutations has been reviewed recently.[145] Another exciting area of aminoglycoside research is the application of aminoglycoside-based compounds in the treatment of HIV.[144] Other strategies in the development of aminoglycosides correspond to the search for compounds with decreased toxicity (for instance derivatives that are specific for their target RNA sequences) and able to combat resistant strains and even the evolutionarily driven development of resistance.[144]
A speculative avenue which could be (or unconfirmed) confirmed in the next 5 years, is the benefit of ceftriaxone in amyotrophic lateral sclerosis, a fatal neurodegenerative disorder for which there is no known cure.
Long-term use of antibiotics poses the problem of reduced susceptibility of potentially pathogenic microorganisms. The results of a few randomized clinical trials have been reviewed recently.[146] Erythromycin resistance of S. aureus in the sputum isolates of CF patients receiving azithromycin for more than 1 year, increased from 6.9% at the beginning of study to 53.8% after 5 years follow-up, and a tenfold increase in clarithromycin resistance in Haemophilus influenzae isolates was observed. Similarly, macrolide resistance has been detected in all S. aureus isolates obtained from CF patients after azithromycin treatment with a mean duration of 3.5 years, and the emergence of macrolide-resistant S. pneumoniae has been reported in 98.2% of pneumococcal isolates recovered from 57 CF patients after 4 years of erythromycin or clarithromycin treatment.[146]
Alternative treatments are required such as erythromycin A derivatives devoid of antibiotic properties, while keeping the immunomodulatory profile. This has been achieved with EM201 and EM703, two erythromycin A derivatives[147] and CSY00073, a nonantibiotic derivative of azithromycin,[148] still in preclinical studies.
Similarly, nonantibiotic chemically modified tetracyclines, were developed to inhibit tumor growth and metastases. Other applications of these cycline derivatives could concern acute coronary syndrome. A recent issue of pharmacological research[149] emphasizes the multiple mechanisms by which nonantimicrobial tetracyclines may be cardioprotective.
With regards to viruses and antiviral agents, three main points can be envisaged in the next years. First, the near future in combating viral diseases stands on a conceptual, 'idyllic' approach, which relies on pathogen extinction. After the global eradication of smallpox in 1979, the concept of 'eradication' has been proposed as the extinction of a pathogen in man as well as in nature. Soon after, the feasibility to eradicate poliomyelitis was considered: in 2011, only four countries (Afghanistan, India, Nigeria and Pakistan) remain polio endemic, down from more than 125 in 1988.[205] Other targets are measles, mumps and rubella. However, eradication may appear more difficult and controversial in a changing world. Global eradication of a disease requires a major public health effort and sparks off controversies in the scientific community. "For some diseases eradication may make sense. But for other diseases, such as polio, measles, mumps and malaria, the dream of eradication may not be one that can be relied upon. The best that may be done is to seek elimination or control rather than eradication and to hope that politics, war, climate change, economics and ethics allow us to get that far".[150]
Second, available antiviral drugs are highly pathogen-specific. Compounds with broad-spectrum antiviral activity, such as dsRNA activated caspase oligomerizers which are effective against different viruses represent a future research strategy, along with nonspecific immunomodulators.
Last, inflammation plays a central role in the pathogenesis of various viruses and the link between autoimmunity and infectious agents has been strongly suggested.[151] This hypothesis has provided the basis for a discussion about the rationale of antiviral compounds in autoimmune diseases. Advances in the fundamental knowledge of autoimmunity, discovery of (new?) viruses responsible for cancer, and inflammatory diseases, may give opportunities to extend the spectrum of activity of antivirals to wider therapeutic approvals.
Expert Rev Anti Infect Ther. 2012;10(3):319-340. © 2012 Expert Reviews Ltd.
