Reaction: Alternative Modalities to Address Antibiotic-Resistant Pathogens
2017; Elsevier BV; Volume: 3; Issue: 3 Linguagem: Inglês
10.1016/j.chempr.2017.08.017
ISSN2451-9308
Autores Tópico(s)Antimicrobial Resistance in Staphylococcus
ResumoFabio Bagnoli is discovery project leader of research & development vaccine programs at GSK. He has served as editor of several publications and is the coordinator of an industrial-academic effort on human organotypic models. He holds a PhD from the University of Padova and conducted post-doctoral studies at Stanford University.David Payne is vice president and head of the Antibacterial Discovery Performance Unit at GSK. He is also principle investigator of GSK's partnerships with BARDA and the Defense Threat Reduction Agency. David holds a PhD and DSc from the University of Edinburgh and has authored >200 conference presentations, abstracts, and publications. Fabio Bagnoli is discovery project leader of research & development vaccine programs at GSK. He has served as editor of several publications and is the coordinator of an industrial-academic effort on human organotypic models. He holds a PhD from the University of Padova and conducted post-doctoral studies at Stanford University. David Payne is vice president and head of the Antibacterial Discovery Performance Unit at GSK. He is also principle investigator of GSK's partnerships with BARDA and the Defense Threat Reduction Agency. David holds a PhD and DSc from the University of Edinburgh and has authored >200 conference presentations, abstracts, and publications. Antibiotics have greatly improved the health and longevity of human beings; nonetheless, infectious diseases still cause a significant burden of mortality worldwide. In addition, antimicrobial resistance (AMR) is quickly increasing, and deaths due to infections have been predicted to exceed those caused by cancer by 2050 (https://amr-review.org/Publications). The US World Health Organization (http://www.who.int/mediacentre/news/releases/2017/bacteria-antibiotics-needed/en/) and the Centers for Disease Control and Prevention (https://www.cdc.gov/drugresistance/biggest_threats.html) recently listed a total of 18 human pathogens with threatening drug-resistance patterns (e.g., Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacteriaceae, Enterococcus faecium, Staphylococcus aureus, Clostridium difficile, and Neisseria gonorrhea). New-generation antibiotics, vaccines, and antibody-based biologics can all contribute to the response to the global challenge of antimicrobial-resistant pathogens. Indeed, none of the three technologies alone has a sufficient chance of succeeding against such an enormous threat. The immediate and logical reaction to the emergence of AMR has been the quest for new antibiotics and innovative ways of searching for and developing new drugs, especially against multidrug-resistant (MDR) bacterial pathogens (see "Catalyst: The Role of Chemistry in Delivering the Next Generations of Antimicrobial Drugs" by Micha Fridman in the July issue of Chem). However, scientific challenges, clinical and regulatory hurdles, and low return on investment have led many companies to abandon the race. Genome-based high-throughput screens for identifying new compounds were run across the industry, but these huge efforts were disappointing. Few potential candidates were identified, and combining antibiotic activity with drugability (i.e., solubility, safety, pharmacokinetics, potency, selectivity, and spectrum) was in most cases an insurmountable obstacle.1Payne D.J. Miller L.F. Findlay D. Anderson J. Marks L. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2015; 370: 20140086Crossref PubMed Scopus (57) Google Scholar, 2Payne D.J. Gwynn M.N. Holmes D.J. Pompliano D.L. Nat. Rev. Drug Discov. 2007; 6: 29-40Crossref PubMed Scopus (1973) Google Scholar, 3Tommasi R. Brown D.G. Walkup G.K. Manchester J.I. Miller A.A. Nat. Rev. Drug Discov. 2015; 14: 529-542Crossref PubMed Scopus (384) Google Scholar Even though this challenge was realized almost 20 years ago, there are still no rational solutions to increasing the success of high-throughput screening of antibacterial targets to deliver quality starting points for novel antibacterial programs. Progress on understanding how to design compounds that optimally penetrate Gram negatives has started in public-private partnerships such as TRANSLOCATION, but much of the success of antibacterial lead optimization remains dependent on the researcher's intuition and trial and error. Clinical trials required for achieving indications in both the US and EU for novel antibiotics are large and challenging to conduct. For example, clinical trials necessary for creating a sufficient data package for supporting the introduction of a novel antibiotic against Gram-negative nosocomial pneumonia were estimated to take an excess of 4 years and cost more than £100 million.1Payne D.J. Miller L.F. Findlay D. Anderson J. Marks L. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2015; 370: 20140086Crossref PubMed Scopus (57) Google Scholar Progress is being made with precedence for streamlined regulatory "limited-use" paths for severe and life-threatening MDR Gram-negative infections. Global alignment on regulatory requirements would create much-needed simplicity for clinical trials, and it is encouraging that the European Medicines Agency, US Food and Drug Administration, and Japanese Pharmaceuticals and Medical Devices Agency are meeting to discuss the convergence of data requirements (http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/06/news_detail_002763.jsp&mid=WC0b01ac058004d5c1). Public-private partnerships have underpinned many companies' ability to continue antibiotic research & development (R&D) and have allowed research into these challenges to continue. For example, New Drugs for Bad Bugs (ND4BB) incorporates clinical-trial networks (e.g., COMBACTE), early discovery programs (ENABLE), and fundamental research to improve our understanding of how to design antibiotics for Gram negatives (TRANSLOCATION). In addition, BARDA and more recently CARB-X are also providing significant funding to small and large companies, which has been critical for the progression of many antibiotics in the current industry pipeline. Although these initiatives have provided significant help, it seems unlikely that investing only in the R&D of new antibiotics is the sole solution to addressing the challenge of AMR. Parallel development of vaccines and antibody-based biologics for the prevention of infections will significantly increase our ability to create a sustainable solution to AMR. AMR can emerge very rapidly, and one of the strongest examples in the field about this phenomenon is given by S. aureus. Resistance to penicillin and methicillin, for instance, was observed approximately 1 year after the commercial introduction of the two antibiotics.4Pozzi C. Olaniyi R. Liljeroos L. Galgani I. Rappuoli R. Bagnoli F. Curr. Top. Microbiol. Immunol. 2017; https://doi.org/10.1007/82_2016_54Crossref PubMed Scopus (33) Google Scholar In contrast, resistance to vaccines is a very rare phenomenon5Kennedy D.A. Read A.F. Proc. Biol. Sci. 2017; 284: 284Crossref Scopus (86) Google Scholar, 6Mishra R.P. Oviedo-Orta E. Prachi P. Rappuoli R. Bagnoli F. Curr. Opin. Microbiol. 2012; 15: 596-602Crossref PubMed Scopus (80) Google Scholar and has been described with sufficient evidence only for the vaccine against the hepatitis B virus (HBV). However, the emergence of resistance to the HBV vaccine has been slow, and the vaccine has almost eradicated the infection from many countries.7Lazarevic I. World J. Gastroenterol. 2014; 20: 7653-7664Crossref PubMed Scopus (97) Google Scholar Another potential case of resistance, which has yet to be demonstrated, is the acellular vaccine against Bordetella pertussis. On the other hand, if vaccine coverage is limited, then serotypes not included in the vaccine can emerge under its selective pressure. After the introduction of the seven-valent pneumococcal vaccine (PCV7), an increase in serotype 19A (not in the vaccine) was observed in patients.6Mishra R.P. Oviedo-Orta E. Prachi P. Rappuoli R. Bagnoli F. Curr. Opin. Microbiol. 2012; 15: 596-602Crossref PubMed Scopus (80) Google Scholar However, this phenomenon is different from vaccine resistance. The low propensity of vaccines to generate resistance is expected to be due to the following factors: they usually target multiple epitopes (several mutations need to accumulate for generating resistance); they prevent pathogen dissemination at the initial phases of the interaction with human tissues, and therefore the microbes have limited time to develop mutations; their effect is durable and also works by herd immunity, further preventing the spread of resistance strains; and the use of different vaccines in veterinary medicine and in animal farming avoids the potential spread of resistant variants from animals to humans. Vaccines can reduce the emergence of antibiotic resistance both directly and indirectly. Directly, by preventing bacterial infections, they can limit the spread of the pathogen (including antibiotic-resistant strains) and limit the use of antibiotics for their treatment. The effectiveness of this mechanism has been demonstrated for PCV7, which has been shown to decrease the rise of antibiotic resistance and the use of primary and secondary antibiotics. Other vaccines (e.g., for Haemophilus influenzae, varicella zoster, and influenza) have shown similar effects.6Mishra R.P. Oviedo-Orta E. Prachi P. Rappuoli R. Bagnoli F. Curr. Opin. Microbiol. 2012; 15: 596-602Crossref PubMed Scopus (80) Google Scholar Indirectly, herd immunity (including the reduction of infection in immunocompromised, elderly, and cancer patients) and vaccines that prevent viral infections also reduce the inappropriate use of antibiotics and bacterial superinfections requiring antibiotics (e.g., influenza vaccines can prevent Streptococcus pneumoniae or S. aureus infections from occurring after influenza infection8Rynda-Apple A. Robinson K.M. Alcorn J.F. Infect. Immun. 2015; 83: 3764-3770Crossref PubMed Scopus (187) Google Scholar). Unfortunately vaccines against major antimicrobial-resistant pathogens are missing, and several development attempts (e.g., S. aureus and P. aeruginosa) have recently failed. Research for developing vaccines against these pathogens is ongoing, and significant advances in the ability to identify potential vaccine candidates by in silico analysis of a pathogen's genome (reverse vaccinology), proteomics, and immunomics approaches increase the likelihood of success. However, reliable animal models and the lack of known correlates and in vitro surrogates of protection are major challenges for vaccine discovery of several pathogens (e.g., S. aureus, P. aeruginosa, N. gonorrhoeae, C. difficile, and Escherichia coli). Significant obstacles for developing these vaccines are also at the level of clinical development. Indeed, without established correlates of protection, very large trials (with several thousand patients) might be needed to confirm the efficacy of candidate vaccines in humans. Therefore, it is very important and urgent that surrogates of protection be established. Obviously the lengthy and complex R&D studies required for the development of a new vaccine for antimicrobial-resistant microbes translate into very high costs for developers. Furthermore, vaccine prices are relatively low, and one course is often sufficient to confer lifelong protection. In addition, use of vaccines against nosocomial pathogens can be restricted to hospitalized patients, significantly reducing the number of recipients who could benefit from these vaccines, returns for the companies, and impact on AMR blockage. Antibody therapy with sera developed against Corynebacterium diphteriae and Clostridium tetani toxins was introduced by Emil Behring at the end of the 19th century. This approach was then largely abandoned after the introduction of antibiotics in the 1940s. Today, after the introduction of monoclonal antibodies (mAbs) and other antibody-based biologics, which do not present the safety issues often associated with the use of polyclonal sera (serum sickness), antibody therapy is experiencing a renovated interest.9DiGiandomenico A. Sellman B.R. Curr. Opin. Microbiol. 2015; 27: 78-85Crossref PubMed Scopus (63) Google Scholar Furthermore, fully human mAbs with even less toxicity and immunogenicity than previously observed with mAbs isolated from other species can now be developed. Several mAbs are being pursued in clinical studies against different pathogens (i.e., viruses: Ebola, hepatitis B and C, Hendra, herpes simplex, HIV, influenza, and rabies; bacteria: S. aureus, C. difficile, E. coli, P. aeruginosa, and Clostridium botulinum). However, as of today, only five mAbs against four human pathogens (i.e., Bacillus anthracis, C. difficile, respiratory syncytial virus [RSV], and rabies) have been licensed or approved. The RSV vaccine was licensed in the late 1990s, yet the other two mAbs have been licensed or approved only very recently. Therefore, given the few mAbs available, we don't yet have enough data to understand the resistance mechanisms that they might trigger. However, given that mAbs target one or few epitopes and that their effectiveness is strictly associated with the affinity toward the target antigen, a few mutations in the recognized epitope could be sufficient to cause resistance. Similarly to what has been discussed for vaccines, we can assume that the use of mAbs has the potential to decrease the emergence of antibiotic resistance by reducing the use of antibiotics both directly (by targeting bacterial pathogens) and indirectly (when the mAb is used to target viruses). Antibody research and development share many of the challenges described for vaccines, but they differ in some key aspects. First of all, whereas vaccines are typically used prophylactically, mAbs are generally considered more appropriate for therapeutic approaches given that they cannot generate memory response. However, specific mutations in the Fc region of mAbs have recently increased their half-life to approximately 3 months, which would allow a sufficient prophylactic coverage in certain settings (e.g., long-term hospitalized patients). In addition, they could be used for preventing infections in certain high-risk groups (e.g., mechanically ventilated patients in intensive care units [ICUs]10François B. Barraud O. Jafri H.S. Clin. Microbiol. Infect. 2017; 23: 219-221Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). For avoiding resistance phenomena and increasing protective efficacy and coverage, multiple epitopes and antigens are usually needed. Although the inclusion of several antigens in a vaccine (e.g., available pneumococcal vaccines contain 13 or 23 different antigens) is feasible with the available technologies, it is difficult to develop combinations of more than two mAbs. Indeed, although the production of mAbs has recently undergone significant improvements (high-performing media, better cell lines, improvements in bioreactor and purification processes), and antibodies with increased affinity have recently been developed (allowing the amount given to the patients to be lowered), they still need to be administered at relatively high concentration (several mg/kg). This presents two major obstacles for developing antibody combinations: high costs of production and limitations in the amount possibly given to the patient (too much antibody administered to the patient could increase reactogenicity). Bispecific mAbs that target two different epitopes are a potential alternative to combinations. Precedence exists with MEDI3902 for P. aeruginosa,9DiGiandomenico A. Sellman B.R. Curr. Opin. Microbiol. 2015; 27: 78-85Crossref PubMed Scopus (63) Google Scholar but engineering such mAbs is complex and requires expanded discovery timelines. Vaccines and antibody-based biologics, however, cannot replace antibiotics for several reasons. They have different and complementary roles in the fight against infections (Table 1). Antibodies and antibiotic effects are immediate or take a few hours, whereas vaccines need a few days or weeks to mount a protective response. Antibiotics are generally used for therapeutic approaches because often the causative pathogen is not known and diagnostics are not sufficiently rapid to identify the infecting agent before the start of treatment. Whereas vaccines are slow, mAbs offer rapid protection from infection and could be the most appropriate approach for patients at high risk of a specific infection (e.g., a ventilated patient who is colonized with P. aeruginosa or a patient who has already had a primary C. difficile infection and needs protection against recurrent infection). Furthermore, vaccines and antibodies have a specific target (reducing the risk of altering the microbiome) and impose less selective pressure for resistant variants on different species. Antibodies against toxins can immediately block major pathogenic symptoms even when the infection is recalcitrant to antibiotic treatment (e.g., anti-alpha toxin antibodies for antibiotic-resistant S. aureus11Bagnoli F. Virulence. 2017; : 1-6Crossref PubMed Scopus (8) Google Scholar). The clear advantage of vaccines over mAbs and antibiotics is that they induce an immunity that can last for several years or be lifelong, can eradicate the pathogen from endemic regions, are able to induce herd immunity, and have a longevity guaranteed by the elusion of resistance mechanisms.Table 1Major Features of Antibiotics, mAbs, and VaccinesFeatureAntibioticsmAbsVaccinesBlocking of emergence or increase in AMRnoyes (directly and indirectly)yes (directly and indirectly)Coverage (specificity)broad (indiscriminate)narrow (very specific)narrow (very specific)Durability of protectionrestricted to the time of treatmentup to a 6 monthsfrom several months to lifelongEfficacious in immune-compromised patientsyesyes (if antibody mediated)not directly but yes indirectly (by herd immunity)Herd or community effectnonoyesLongevity (time for resistant strains to emerge)a few yearsunknownmany years to unlimitedMicrobiome alterationyesno (if not against commensal flora)no (if not against commensal flora)Pathogen eradication from endemic regionsnonoyesPricea few to thousands of dollars per therapy (depends on the length of the therapy)several thousand dollarsa few dollars to around $200 (one or few immunizations can be sufficient for lifelong protection)Resistancecommon (can be rapid during therapy)unknown (may depend on whether there is dual targeting)very rareSelective pressurehigh if given therapeutically (they act on a large number of bacteria)low if given prophylactically (they act on a small number of bacteria) andhigh if given therapeutically (they act on a large number of bacteria)low if given prophylactically (they act on a small number of bacteria)Therapeutic and/or prophylacticmostly therapeuticboth therapeutic and prophylacticmostly prophylacticTreatment or prevention of viral infectionsnoyesyes Open table in a new tab In conclusion, the three big anti-infective companions, which have largely been used for different purposes so far, together present great opportunities for addressing AMR. Vaccines play a key role in reducing infections that affect large populations but should now also be considered as providing protection against hospital-acquired infections. A paradigm for consideration is one where patients entering a high-risk situation (e.g., a patient moving into an ICU or likely to be on a ventilator) could be dosed with a mAb for rapid protection and then a subsequent vaccine for long-term protection. Antibiotics will remain critical for treating (and in some cases preventing) infections given that broad-spectrum coverage is initially needed for ensuring that all causative pathogens are covered until the infecting pathogen is identified. Parallel development of rapid, accurate, and cost-effective point-of-care diagnostics will be key to ensuring that antibiotics and mAbs are used in the appropriate clinical situations and play a fundamental role in the overall control of AMR. These approaches entail significant challenges in R&D, and it is very unlikely that the solution will come from just one of these technologies. The wiser approach is based on coordination of the effort done on the three platforms for ensuring that the most suitable technology is developed for the different pathogens. Public-private partnerships for promoting such an effort would be beneficial to the field. This work was funded by GlaxoSmithKline (GSK) Biologicals SA. F.B. and D.P. are employees of the GSK group of companies and are listed as inventors on patents owned by the GSK group of companies. They report ownership of GSK stocks. The authors thank Carine Goraj and Ennio De Gregorio at GSK for critical reading of the manuscript. Catalyst: The Role of Chemistry in Delivering the Next Antimicrobial DrugsMicha FridmanChemJuly 13, 2017In BriefMicha Fridman is an associate professor of chemistry at Tel Aviv University. He earned his PhD at the Technion-Israel Institute of Technology (2005) and was a postdoctoral fellow at Harvard University (2008). His research focuses on studying the mode of action of antimicrobial agents and on exploring novel approaches and cellular targets for the development of antibacterial and antifungal drugs. Full-Text PDF Open ArchiveReaction: Broad-Spectrum Antibiotics, a Call for ChemistsRichter et al.ChemJuly 13, 2017In BriefMichelle F. Richter received her BS in biochemistry from Union College in 2011. She is now a National Science Foundation graduate fellow and member of the NIH Chemistry-Biology Interface Training Program in the Hergenrother laboratory at the University of Illinois at Urbana-Champaign (UIUC), where she is working toward a PhD in chemistry. Paul J. Hergenrother received his BS in chemistry from the University of Notre Dame in 1994 and his PhD in chemistry at the University of Texas at Austin in 1999. After an American Cancer Society postdoctoral fellowship in the laboratory of Prof. Stuart Schreiber at Harvard University, in 2001 he joined the faculty at UIUC, where he is now the Kenneth L. Rinehart Jr. Endowed Chair in Natural Products Chemistry. Full-Text PDF Open ArchiveReaction: Molecular Modeling for Novel AntibacterialsDenis FourchesChemJuly 13, 2017In BriefDenis Fourches, PhD, is a molecular modeler and expert in cheminformatics in the Department of Chemistry and the Bioinformatics Research Center at North Carolina State University. His research focuses on the development and applications of novel predictive cheminformatics methods. Full-Text PDF Open Archive
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