S. aureus, cultured on an agar plate containing antibiotics. Source: CDC Public Health Image Library
Drug resistant bacteria is a growing problem, claiming an estimated 23,000 deaths per year in the USA. In light of this, new research into next generation antimicrobicides has produced a therapy that holds promise in the near-term: augmenting the traditional cocktail of broad-spectrum antibiotics with polyclonal IgG. The addition of polyclonal IgG is potent enough to galvanize antibacterial monotherapies that are currently deemed ineffective against drug resistant infections.1
Biologics have proven to be capable of immune-system independent antimicrobial activity, making them an area of increasing interest amidst the spread of drug resistance.2 The treatment strategy outlined in the new research is especially appealing, as it makes use of inexpensive common antibiotics and polyclonal IgG, all of which are well understood and have been used in other therapeutic indications. The trick here will be finding a program that is capable of formulating and modeling this wealth of new information in a way that cuts down on lost time and decreases errors so that lives can start benefiting from this new therapy.
The antibacterial cocktail of the future
In order to combat widespread multi-drug resistant bacteria, multiple treatment strategies will be used in conjunction simultaneously. Unlike the current treatment strategy of progression from weaker antibiotic small molecules to stronger antibiotics served in a cocktail,3 the lesson learned from the bacterial drug resistance epidemic is clear: as soon as drug resistance is suspected, treatment must immediately escalate to deployment of multiple powerful drugs with distinct mechanisms of action 4 Until now, adding additional small molecule antibiotics was the only course of action, leading to an ever-increasing proliferation of drug resistance.
The new research provides a glimpse into the methodology that future drug resistant antibacterials will use. The data show that polyclonal IgG synergistically enhances the bactericidal effects of traditional antibiotics to the point of overpowering drug resistance, guaranteeing that the antibacterial cocktail of the future will look a lot like the cocktail of the past, only with the addition of biologics. The biologics used in the cocktail will ultimately be a mix of IgG and monoclonal antibodies against specific bacterial targets. It remains to be seen whether the effect of monoclonal antibody binding to bacterial capsids will also synergize with traditional small molecules and polyclonal IgGs, and this will be a major point of interest in future research.
This promising possibility is not without its obstacles, however. It’s clear that the usage of multiple biologics in addition to small molecule antibacterials complicates the treatment process substantially. Potential points of synergy or incompatibility between elements of the next generation antibacterial cocktail have yet to be studied beyond the new research’s in vitro examination of IgG’s synergy with vancomycin, amoxicillin, clarithromycin, and azithromycin. Importantly, these small molecules were tested individually in conjunction with IgG rather than as a cocktail, as they would be used in cases of multiple-drug resistant infection.
Thus, any new antibiotic biologics will require a substantial amount of research into how they perform combinatorially before they can make it into the clinic. In-house efficacy profiles will need to be generated for:
- Individual small molecules, including those known to be ineffective against drug resistant infections
- Multiple simultaneous small molecules
- Individual small molecules in conjunction with IgG
- Multiple simultaneous small molecules in conjunction with IgG
- Timing of IgG infusion relative to individual and multiple small molecule dosage
- Monoclonal antibodies in isolation
- Monoclonal antibodies in conjunction with individual and multiple small molecules
- Monoclonal antibodies in conjunction with IgG
- Timing of monoclonal antibody administration relative to IgG infusion
- Monoclonal antibodies in conjunction with both individual and multiple small molecules as well as IgG
The amount of efficacy profiles needed expands exponentially with the number of different small molecule and biologic therapies that are included in the hypothetical cocktail. The most effective cocktail will include many different antibacterial elements which operate on distinct targets, meaning that the complexity of drug development targeting drug resistant infections will expand substantially. This poses a prickly problem for anyone developing a new hypothetical antibacterial biologic. Given that biologic development is already quite difficult, combatting drug resistant infections via biologics will require a powerful research platform.
Monoclonals join the fight
Monoclonal antibodies have long been recognized as a potential capstone in antibacterial drug development.5 Only recently has the development of monoclonals been made easier by powerful software packages and other antibody generation methodologies. With the advancement of technology, the challenges of monoclonal generation have shifted, requiring an abundance of pre-experimental binding engineering and protein simulation. Monoclonals intended for use as antibacterials alone or in cocktails are no exception, and face additional challenges during development.
Beyond monoclonal antibody development for other purposes, monoclonals generated for use in a multiple drug resistant antibacterial cocktail must be able to overcome the following challenges:
- Localization to infection site
- Durability at infection site
- Lack of consistent binding sites on the bacterial capsid
- Binding sites on bacterial capsid changing due to selective pressure of treatment
- Binding site blockage by cytoplasmic bacterial organelles
- Infection microenvironment potentially containing different pH than normal, changing binding characteristics
- Infection microenvironment potentially containing binding-blocking biofilms6
- Binding site blockage or occupancy by other elements of the cocktail, particularly IgG
- Insufficient post-treatment activation of the weakened host immune system due to failed first or second line treatments
- Few off-target effects caused by insufficient antibody specificity that would weaken the patient’s already compromised health further
- Few on-target yet orthogonal to treatment effects that would cause downstream physiological changes and weaken the patient further
Ample in silico simulation and experimentation before moving into the laboratory is necessary to avoid falling victim to the many pitfalls of biologic development. Simulating the following will prove to be especially fruitful:
- Polyclonal IgG binding to the bacterial capsid
- Monoclonal IgG binding to the bacterial capsid
- Mono- and polyclonal conformational structure at the projected infection microenvironment
- Genetic drift caused by selective pressure of previous treatments
- Genetic drift caused by selective pressure of cocktail treatment
Approaching development of a monoclonal antibody without a powerful software platform is especially difficult when generating an antibody that has to be compatible with a variety of other treatment elements. Most biologic development platforms aren’t up to the task of integrating the substantial number and depth of properties that are required in the development of antibodies intended for use in drug resistant bacterial infections. Thankfully, there is an information technology solution that lives up to such intense demands and can be instrumental in saving the lives of patients who will benefit from this new treatment option.
BIOVIA Biologics is the antibody design studio that includes all of the simulation and data tracking tools required to address the problem of multiple drug resistant bacterial infections. Using BIOVIA Biologics, your biologic development process will be accelerated, simple, and effective. Contact us today to find out how we can help you get involved in developing the antibacterial biologics of the future.
- “A novel combination approach of human polyclonal IVIG and antibiotics against multidrug-resistant Gram-positive bacteria.” December 2016, https://www.ncbi.nlm.nih.gov/pubmed/27994476 ↩
- “A monoclonal antibody directed against a Candida albicans cell wall mannoprotein exerts three anti-C. albicans activities.” September 2003, http://iai.asm.org/content/71/9/5273.long ↩
- “General Principles of Antimicrobial Therapy.” February 2011, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031442/ ↩
- “In Vitro Activities of Quinupristin-Dalfopristin and Cefepime, Alone and in Combination with Various Antimicrobials, against Multidrug-Resistant Staphylococci and Enterococci in an In Vitro Pharmacodynamic Model.” August 2002, http://aac.asm.org/content/46/8/2606.long ↩
- “Antibacterial monoclonal antibodies and the dawn of a new era in the control of infection.” 1984, https://www.ncbi.nlm.nih.gov/pubmed/6438759 ↩
- “Microenvironment and microbiology of skin wounds: the role of bacterial biofilms and related factors.” September 2015, http://www.semvascsurg.com/article/S0895-7967(16)00004-1/pdf ↩