[authors: David Puleo and Anthony D. Sabatelli]

Antibiotic resistance is a major problem in the United States and is considered by the World Health Organization (WHO) to be one of the largest threats to human health.  The top 12 bacterial threats classified by WHO are shown in Table 2¹.  Researchers are going so far as to send antibiotic resistant bacteria into space in order to determine how the bacteria mutate, with the thought being that in space, bacteria will mutate at an accelerated rate, making it easier to study bacterial resistance patterns and, therefore, develop better antibiotics that are active against resistant bacterial forms.

Government-run institutions are investing significantly in the study of antibiotic resistance and resistance mechanisms.  For example, in early 2015, the White House released its "National Action Plan For Combating Antibiotic-Resistant Bacteria".  Similarly, in 2016, the CDC passed the Antibiotic Resistance Solutions Initiative, allocating roughly $160 Million in order to "detect, respond, and contain resistant infections across healthcare setting and communities."²  The CDC also awarded $14 Million to 34 different projects that will further investigate antibiotic resistance as it relates to the microbiome.  Yale University is one of the institutions to which funds were given.  This article will review antibiotic resistance, how antibiotics affect the microbiome, and those therapeutic strategies being used to prevent or correct microbiome imbalances.  Furthermore, we will review some of the significant players and patents in this area.

Problems with Antibiotic Use

Research published in the Journal of the American Medical Association (JAMA 2016, 315: 1864-73) suggests that antibiotics were prescribed unnecessarily in roughly 30% of patient cases.  This unwarranted exposure to antibiotics, as well as the misuse, overuse, or incorrect prescription of antibiotics, increases the likelihood of developing resistance.  Specifically, the majority of nosocomial (hospital-related) infections are caused by so-called ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species).  These "opportunistic infections" are especially deleterious for patients who have weakened immune systems, e.g., cancer patients undergoing chemotherapy.

The emergence of resistance can occur via different mechanisms which include, but are not limited to (1) production of efflux, or multi-drug resistance (mdr), pumps that, as the name implies, "pump" out antibiotics that are harmful to the organism; (2) production of enzymes that modify antibiotics and, thus, inactivate them or make them less efficacious; and/or (3) mutation of those enzymes that are the targets of antibiotics, thus allowing those enzymes to evade antibiotics.³  The end result is that those resistant bacteria are able to colonize the host, flourish, and overtake host commensal microbiota.

Combatting Clostridium difficile infection (CDI)

Typically, broad-spectrum antibiotics are prescribed for un-diagnosed conditions as a prophylactic, or preventative, measure.  However, it is common that treatment with broad-spectrums can wipe out an individual's healthy gut microflora and cause microbiome imbalance, or dysbiosis.  This may further predispose patients to infections from MRSA (Methicillin-resistant Staphylococcus aureus), CRE (carbapenem-resistant Enterobacteriaceae), or Clostridium difficile.  Clostridium difficile infection (CDI) is a relatively common and refractory infection, often acquired in hospitals and nursing homes by susceptible elderly patients.  The standard-of-care treatment for CDI is usually treatment with other antibiotics, firstly metronidazole, and if that is not efficacious, vancomycin.  However, one concern with treatment using vancomycin is the emergence of vancomycin-resistant bacteria.

Rather than treating patients with antibiotics, clinicians are turning to a procedure known as fecal microbiota transplant (FMT), whereby fecal bacteria are transferred from a healthy individual to a recipient patient.  The transplant is meant to replenish bacteria that have been depleted from antibiotic treatment in the recipient and, thus, restore eubiosis.  An increased number of patents in this space reflect this trend.  For example, US 9,511,099 refers to the use of a similar methodology, termed Microbiota Restoration Therapy (MRT).  Although mainly used for the treatment of CDI, the patent application also discloses colon cancer.  The company that filed the patent application, Rebiotix, has several therapies in clinical trials for CDI treatment and prevention.  Referenced briefly in Part V of the Microbiome Series, patents US 9,028,841 and US 9,446,080 from Seres Therapeutics were included below, which also disclose methods for the treatment and prevention of recurrent CDI.  Seres's current lead, SER-109, is currently in Phase II clinical trials and has been reviewed earlier here by Dilworth IP.

Another company, OpenBiome (The Microbiome Health Research Institute), is a non-profit organization that is the first public stool bank.  It has patented a capsule containing microbes for the treatment of gastrointestinal disorders (WO 2016/178775).  OpenBiome is also collaborating with Finch Therapeutics on a treatment for CDI.

Alternatives to Antibiotics: Using Immunotherapies to Alter the Microbiome

Although some companies are still focusing their efforts on identifying new antibiotics, others have begun undertaking new approaches.  As mentioned above, in the case of CDI, missing bacteria can be replenished via FMT and, thus, restore a patient to eubiosis.  However, is it possible to remove a specific bacterium from the host commensal population, which would completely eliminate the need for antibiotics?  Numerous companies are attempting just that.  Using their proprietary Cloudbreak™ Immunotherapy Platform, Cidara Therapeutics can selectively target and clear gram-negative bacteria.  Although no patent directed to the Cloudbreak™ Platform could be found, Cidara has patent application US 2016/0213742 for the treatment of fungal infections, specifically from Aspergillus fumigatus and Candida albicans.

MedImmune, the biologics arm of AstraZeneca, has patented several monoclonal antibodies (mAbs) targeting bacterial-specific antigens as a means of selectively clearing bacteria.  Patent US 9,527,905 claims the use of a mAb targeting Staphylococcus aureus α toxin, a component that enhances the proliferation of this Gram-negative bacteria.  The in vivo efficacy of one such mAb, MEDI4893, was described in a 2016 article in Science Translational Medicine [Sci. Transl. Med. 2016, 8: 329ra31].  Another patent application from Arsanis Biosciences, US 2015/0086539, and patent from XBiotech, US 9,486,523, detail mAbs targeting S. aureus.  Patent application US 2015/0284450 describes a bispecific mAb targeting Pseudomonas aeruginosa.  The clinical candidate, MEDI3902, is detailed in the following: Sci. Transl. Med. 2014, 6: 262ra155.  Another anti-P. aeruginosa mAb is detailed in patent US 9,403,901.  A mAb that binds the outer membrane of Acinetobacter baumannii is detailed in patent US 8,747,846.  An anti-Streptococcus pneumoniae mAb is detailed in patent US 9,279,815.

Moving Forward to Combat Resistance

While seemingly attractive years ago, the use of broad-spectrum antibiotics is now being questioned.  A recent paper in Nature Communications (Nat. Commun. 2017, 8: 15062) posits that the use of antibiotics in infants significantly changes their microbiome composition later in life.  Thus, in the short term, determining if and when a patient needs antibiotics will help to limit the spread of resistance.  Although the aforementioned mAb therapeutics may in fact be superior to standard-of-care broad-spectrum antibiotics, whether and how resistance will develop is still a question.  Similarly, the insurance dynamics and cost to the patient may be a significant concern.  As new therapies develop, patent protection will certainly be an integral part of the process.

¹ http://www.who.int/mediacentre/news/releases/2017/bacteria-antibiotics-needed/en/
² https://www.cdc.gov/drugresistance/solutions-initiative/
³ https://www.cdc.gov/getsmart/community/about/antibiotic-resistance-faqs.html

David Puleo is a Ph.D. Candidate in the Pharmacology Department at Yale University.  Prior to attending Yale, David graduated from Boston College with a B.S. in Biochemistry, after which he worked for two years in the Center for Proteomic Chemistry at Novartis Institutes for BioMedical Research in Cambridge, MA.
** Dr. Sabatelli is a Partner with Dilworth IP