A University of Copenhagen chemist, along with physicians from the University of Southern Denmark and King Christian X’s Hospital for Rheumatic Diseases, has developed a drug to combat multidrug resistant tuberculosis (MDR-TB) and other multiple drug-resistant organisms (MDROs). The new medication, JEK 47, is a structural variant of thioridazine hydrochloride, an antipsychotic generally prescribed for schizophrenia patients.
JEK 47 works by inhibiting bacterial efflux pumps, which allows the pathogens to resist antibiotics by increasing the pump’s efficiency. Resistant microorganisms are, in essence, still sensitive to antibiotics; efflux pumps just help bacteria shed bactericidal agents before they can inflict damage. JEK 47 was designed to disable these efflux pumps so that antibiotics have time to work against the pathogens.
Thioridazine hydrochloride, in its currently FDA-approved form, is a treatment for schizophrenia for patients who do not respond to other antipsychotics or cannot tolerate the adverse effects of other related medications. Side effects of thioridazine hydrochloride include twitching, tremors, restlessness, and other nervous system tics. To prevent the likelihood of such effects, the scientists isolated the drug’s isomer, or chiral molecule (virtually a mirror image), that exhibits the same bacteria-killing ability without the adverse effects, and dubbed it JEK 47. Since only a small amount of the medication is required for it to be effective, patients expected to feel a little lethargic at the most.
In 2012, the World Health Organization (WHO) announced people infected with MDR-TB has markedly risen, particularly in Africa and Asia. Tuberculosis (TB) is an airborne infectious disease caused by the bacterium, Mycobacterium tuberculosis, and primarily affects the lungs. Pneumonia develops and symptoms of chest pain and persistent cough ensue, with hemoptysis (coughing up blood) in later stages. Treatment entails a cocktail of antibiotics for six months to a year.
The researchers hope JEK 47 can eliminate the need for prolonged treatment of MDR-TB and decrease the disease’s worldwide prevalence, especially in developing nations where MDROs are a life-threatening issue even without the presence of MDR-TB.
Since the advent of antibiotics, bacterial infections were no longer considered a death sentence. However, through overuse; microorganisms’ natural defense systems; and, medications’ unimodal mechanism of action, multiple drug-resistant organisms (MDROs) have emerged and are threatening human lives once again. Danish and Canadian scientists from the University of Copenhagen and the University of British Columbia, respectively, have engineered a synthetic peptide called host defense peptidomimetic 4 (HDM-4) that displays broad-spectrum antibacterial properties.
HDM-4 works by creating holes in the cell membrane of a bacterium and binds to the pathogen’s deoxyribonucleic acid (DNA) causing microbial death. HDM-4 also rapidly permeates bacterial cells and attaches to DNA in small lethal concentrations. The original peptide HDM-4 is modeled after is naturally found in animals and plants as part of the innate immune system—the first line of defense against pathogens before antibodies are formed. HDM-4 was found to enhance this immune response for superior pathogenocide.
When tested on bacteria-infested tissue, the synthetic peptide worked effectively against Gram-negative species and interfered with biofilm formation—a sugary bubble that bacteria build to protect themselves enabling them to reproduce and multiply. Due to the many ways HDM-4 goes about killing microbes, drug resistance is suspected to be low, thus hindering the progression of more potent bacteria while efficiently killing MDROs.
The scientists believe the creation of HDM-4 is an important component in developing a new type of antibiotic that prevents MDROs. However, there are barriers to furthering such research as pharmaceutical companies consider drugs for chronic diseases, such as diabetes and cardiovascular disorders, and cancer better long-term investments than the treatment of infectious diseases.
Medical conditions, such as sepsis or “blood poisoning,” can benefit from new medications that can quickly treat life-threatening diseases, albeit further research is required to discover any harmful side effects which require human trials. But, such findings are a crucial step in countering the ever-present war against infectious diseases. Hopefully, there will be champions to take up the cause.