Novel compounds to treat antibiotic-resistant clinical isolated pathogens
Israel Nisan, Noa Tejman Yarden, Yaakov Davidov, Galia Rahav , Sheba Medical Center
Antibiotics, composition, drug resistant, infection disaeses,
The rapid emergence of resistant bacteria is occurring worldwide, endangering the efficacy of antibiotics, which have transformed medicine and saved millions of lives. Many decades after the first patients were treated with antibiotics, bacterial infections have again become a threat. The antibiotic resistance crisis has been attributed to the overuse and misuse of these medications, as well as a lack of new drug development by the pharmaceutical industry due to reduced economic incentives and challenging regulatory requirements. The Centers for Disease Control and Prevention (CDC) and the WHO have classified a number of bacteria as presenting urgent, serious, and concerning threats, many of which are already responsible for placing a substantial clinical and financial burden on the world health care systems, patients, and their families.
Among gram-positive pathogens, a global pandemic of resistant Staphylococcus aureus (MRSA, MSSA) and Enterococcus species currently poses the biggest threat. MRSA kills more Americans each year than HIV/AIDS, Parkinson’s disease, emphysema, and homicide combined. Vancomycin-Resistant Enterococci (VRE) and a growing number of additional pathogens are developing resistance to many common antibiotics. The global spread of drug resistance among common respiratory pathogens, including Streptococcus pneumoniae and Mycobacterium tuberculosis, is epidemic.
Gram-negative pathogens are particularly worrisome because they are becoming resistant to nearly all the antibiotic drug options available, creating situations reminiscent of the pre-antibiotic era. The emergence of MDR (and increasingly pan-resistant) gram-negative bacilli has affected practice in every field of medicine. The most serious gram-negative infections occur in health care settings and are most commonly caused by Enterobacteriaceae (mostly Klebsiella pneumoniae), Pseudomonas aeruginosa, and Acinetobacter. MDR gram-negative pathogens are also becoming increasingly prevalent in the community. These include extended-spectrum beta-lactamase-producing Escherichia coli and Neisseria gonorrhoeae.
We have identified and isolated a unique bacterial species, superbug 007 that belong to the Betaproteobacteria class, gram negative and motile bacteria.
We characterized our isolates and demonstrated their antibacterial activities, killing or inhibiting the growth of different clinical pathogenic isolates including Staphylococcus aureus (MRSA, MSSA), Vancomycin resistant Enterococcus faecalis (VRE), Pseudomonas aureginosa and multidrug resistant Acinetobacter baumannii.
The excessive global use of antimicrobial drugs in humans as well as agriculture and veterinary medicine is followed by the emerging of new multidrug resistant pathogens. Many of these pathogens are globally spread and treatment options for clinicians are limited. Therefore, there is an urgent need for the developments of new antimicrobial drugs.
Key points associated with the reality of (i) the existence of pandrug-resistant bacteria, (ii) the increase of resistance worldwide, (iii) the link between resistance and death, and (iv) the need to develop new antibiotics.
Antibacterial resistance will continue to accumulate in many pathogens and settings, especially in hospitals. The need for new agents is most pressing in hospital infections, where small but growing numbers of isolates, mostly Gram-negative nonfermenters of the genera Acinetobacter and Pseudomonas, are resistant to all ‘good’ antibiotics and where growing numbers of Enterobacteriaceae are resistant to all except carbapenems. Whilst there is a lesser shortage of agents active against Staphylococci, the prevalence of infections with methicillin-resistant Staphylococcus aureus (MRSA) remains extremely high in many countries
The Technology and Innovation
We are in the process of characterizing novel anti-bacterial compounds from new sours:
ü Most of todays' antibiotics are produced by Actinomycetes (gram positive), or by fungi. Recently we have discovered that Superbug 007 are able to kill other bacteria. Therefore our novel Superbug 007 isolates are an important new source for novel antimicrobial compounds.
ü We developed Superbug 007 Selective Agar that was successfully used to isolate various novel Superbug 007 strains.
ü We identified antimicrobial activities against various clinically important pathogens, including Staphylococcus aureus (including clinical isolates of MRSA and MSSA), Vancomicin resistant Enterococcus faecalis (VRE), multidrug resistant Acinetobacter baumannii and Pseudomonas aeruginosa.
ü We optimized growth conditions for maximal secretion of active fraction.
ü We identified a novel family of Non Ribosomal Peptides (NRPs) siderophores with a broad spectrum antimicrobial activity. We extensively characterized compound A activity against MRSA, MSSA & VRE. Moreover, we have demonstrated the plausibility of using compound A as a "Trojan horse", by binding to a toxic molecule (e.g. Gallium) and targeting specific pathogens expressing compound A transporters.
ü In order to isolate the hydrophilic active compounds, we developed isocratic separation technique and isolated several active fractions. We have a potent candidate molecule from one of the fractions. Its chemical formula has been determined and it does not resemble any known molecule. According to its chemical characteristics we believe it is a new member of the zeamine group. Gradually we are narrowing down the amount of compounds in this and other polar fractions by continuous separation while simultaneously continuing to test for activity against our target MDR pathogens.
ü Superbug 007 supernatant is neither toxic nor hemolytic to eukaryotic cells
Superbug 007 bacteria are non- pathogenic gram negative bacteria. To the best of our knowledge, the Superbug 007 sp. has never been used before as a source for antimicrobial compounds. Therefore, the chances are high of discovering novel antimicrobial compounds.
Library of antibacterial Compounds – Novel compositions to treat clinically MDR and XDR pathogens.
The WHO published its first ever list of antibiotic-resistant "priority pathogens" on February 2017:
a catalogue of 12 families of bacteria that pose the greatest threat to human health. The list highlights in particular the threat of gram-negative bacteria that are resistant to multiple antibiotics.
Priority 1: CRITICAL
- Acinetobacter baumannii, carbapenem-resistant
- Pseudomonas aeruginosa, carbapenem-resistant
- Enterobacteriaceae, carbapenem-resistant, ESBL-producing
Priority 2: HIGH
- Enterococcus faecium, vancomycin-resistant
- Staphylococcus aureus, methicillin-resistant, vancomycin-intermediate and resistant
- Helicobacter pylori, clarithromycin-resistant
- Campylobacter spp., fluoroquinolone-resistant
- Salmonellae, fluoroquinolone-resistant
- Neisseria gonorrhoeae, cephalosporin-resistant, fluoroquinolone-resistant
Priority 3: MEDIUM
- Streptococcus pneumoniae, penicillin-non-susceptible
- Haemophilus influenzae, ampicillin-resistant
- Shigella spp., fluoroquinolone-resistan
Our library of molecules are active against
The antibiotics market was valued at USD 29.8 billion in 2015 and is expected to witness a CAGR of 4.0% over the forecast period and is expected to reach USD 39.0 billion by 2024. Increasing efforts are being witnessed toward the development of advanced products. About 37 promising molecules were being investigated within the U.S. market and are anticipated to hit the market between 2018 - 2020. Furthermore, supportive government legislations, such as the Generating Antibiotics Incentives Now (GAIN) Act has provisions which facilitate development of therapy against antibiotic resistant pathogens.
More than 15.0% of the deaths, in children below the age of five, are estimated to be due to pneumonia and according to the statistics provided by the WHO about 9.2 million deaths were recorded in 2015. Antibiotic resistance accounts for 50,000 deaths per year in the US and Europe alone. Routine surgeries and minor infections might become life threatening if novel antibiotics are not developed