THE STATE OF ANTIBACTERIALS
One of the greatest public health challenges of the 21st century is antibiotic resistance, which occurs when a few bacteria in a given population develop a genetic mutation that enables them to survive—even in the presence of antibiotics.
How do bacteria become drug resistant? Suppose a particular antibiotic inhibits an enzyme required for bacterial replication. If one bacterium mutates so the enzyme has a slightly different shape, the antibiotic is no longer effective. The mutated bacterium lives on and continues to replicate, even as all the others die off. Over time, this resistant strain becomes dominant, spreading from person to person, remaining unchecked and thriving. It is not uncommon for a strain of bacteria to become resistant to several different antibiotics, giving rise to the term multi-drug resistant (MDR) bacteria.
One of the most common types of antibiotic-resistant bugs is methicillin-resistant Staphylococcus aureus (MRSA), which typically causes potential life-threatening skin infections. In addition to MRSA, other drug-resistant microorganisms of urgent concern include Clostridium difficile (life-threatening diarrhea), Enterobacteriaceae (bloodstream infections), Neisseria gonorrheoeae (severe reproductive complications), Pseudomonas aeruginosa (pneumonia, bloodstream, urinary tract, and surgical site infections), and Mycobacterium tuberculosis (tuberculosis).
Antibiotic resistance is largely caused by antibiotic overuse—the more a bacterial population is exposed, the greater the probability of mutations. This begs the question: what is the current state of the antibiotic economy?
ON THE MARKET
The last few years have seen several new antibiotics make it to the market. Three for the treatment of acute bacterial skin and skin structure infections, often caused by MRSA, as well as an antibiotic that enhances the effectiveness of its partner antibiotic.
Dalvance (Durata Therapeutics, Chicago, IL) and Orbactiv (The Medicines Company, Parsippany, NJ) work by inhibiting bacterial cell wall synthesis. The cell wall is a layer of sugars and amino acids (peptidoglycans) that surround bacterial cell membranes, providing bacteria with structural support, protection, and a filtering mechanism. These new drugs are a synthetic lipoglycopeptide—a chemical entity similar enough to the peptidoglycans so they are easily incorporated into the cell wall, but different enough so that once integrated, cell wall synthesis stops. Without a functional cell wall, bacteria die. Since human cells do not have cell walls, they are not affected by Dalvance and Orbactiv.
Sivextra (Cubist, Lexington, MA), works by inhibiting bacterial ribosomes—the enzyme that makes all bacterial proteins. Without new protein production, the bacterium is unable to carry out functions essential for life and dies as a result.
Avycaz (Actavis, Parsippany, NJ) is used in combination with a previously approved antibiotic called cephalosporin. Avycaz inhibits the enzyme beta-lactamase, which bacteria secrete in order to break down other antibiotics—essentially boosting the potential of its paired antibiotic.
Although these approvals are encouraging, none work by entirely novel mechanisms so it is likely that resistance will eventually come about—underscoring the continued need to discover and develop antibiotics.
IN THE CLINIC
GlaxoSmithKline (London, UK) has a novel antibacterial compound, Gepotidacin, in Phase II clinical testing. Gepotidacin is a topoisomerase II inhibitor, meaning it inhibits a bacterial enzyme involved in helping bacterial DNA to unwind in order to be replicated. Inhibiting the enzyme impedes bacterial DNA replication. Gepotidacin is being developed in collaboration with the US government’s Biomedical Advanced Research and Development Authority/Defense Threat Reduction Agency.
Spero Therapeutics (Cambridge, MA) is developing a way to more effectively target gram-negative bacteria, or bacteria whose outer membranes contain negatively charged lipopolysaccharides. Lipopolysaccharides are lipid molecules with sugar groups attached, and this combination makes it difficult for antibiotics to penetrate. By developing novel “potentiator” compounds that interact with and disrupt these lipopolysaccharides, Spero scientists hope to make these bacteria susceptible to antibiotics that already exist. Examples of gram-negative bacteria include strains that cause pneumonia, meningitis, urinary infections, and gastrointestinal problems.
Motif Bio (London, UK ) has a novel antibiotic, Iclaprim, in Phase III for acute bacterial skin infections, including MRSA and MDRSP (multi-drug resistant Streptococcus pneumoniae). Iclaprim works by inhibiting an enzyme called DHFR, which plays a key role in bacterial metabolic pathways.
Melinta Therapeutics (Lincolnshire, IL) recently completed Phase III clinical studies for MRSA skin infections with Baxdela, a compound that belongs to an established class of antibiotics, the quinolones. Baxdela works by interfering with bacterial DNA replication. Melinta scientists are also developing novel antibiotics which inhibit the bacterial ribosome—the giant enzyme that synthesizes proteins.
RESEARCH & DEVELOPMENT
Antibiotics have traditionally been found by screening soil bacterium for compounds they release to kill their competitors: other bacteria competing for the same resources. The big problem with this methodology, however, lies in the fact that most soil bacteria do not grow well in the lab—making it impossible to screen 99% of potential candidates.
A team of scientists at Northeastern University (Boston, MA) developed a method of cultivating bacteria in the lab by sandwiching them between layers of the soil separated by a semi-permeable membrane. NovoBiotic Pharmaceuticals (Cambridge, MA) used the technique to screen 50,000 new types of soil bacteria and identified 25 new drug candidates. NovoBiotic’s most promising candidate is Teixobactin, a compound that binds to two different lipid components of the bacterial cell wall, preventing them from being used to produce future cell walls. Neither lipid is rapidly evolving, so it is likely to take a much longer time for resistance to come about. The compound is also highly toxic to bacteria cells, a trait that should also defer resistance by quickly killing off target populations before resistance emerges.
Another large and mostly untapped source of potential new antibiotics are the microbes of the ocean. Because of significant environmental differences in temperature, salinity, and pressure between the ocean and the lab, these microbes can be near impossible to grow outside of the marine environment. University of California San Diego scientists are developing ways to circumvent this plight through genomics. By isolating and sequencing the DNA of marine microbes, researchers identify gene clusters that they predict will code for antibiotic-like compounds. These genes are then transferred and grown in bacteria. One such compound is dubbed taromycin A, which impairs the growth of several types of drug-resistant bacteria, providing a potential platform for future antibiotics.
Another new approach can be found in the immune system of the bacteria itself—the often buzzed about CRISPR/Cas 9. CRISPR stands for “clustered regularly inter-spaced short palindromic repeats.” These are short DNA sequences that read the same forward and backward and are found dispersed throughout the genomes of many types of bacteria. In the mid-2000’s, scientists realized these sequences were a part of the bacterial immune system. Bacteria insert bits of invading viral genomes between the CRISPR sequences. If the bacteria is subsequently infected by the same virus, the previously inserted viral DNA is used to make RNA that recognizes and binds to the invading viral genome—triggering the protein Cas9 to cut up the viral DNA.
Researchers at Tel Aviv University and MIT are working to develop CRISPR/Cas9 systems to target bacteria-encoded antibiotic resistance genes. Their approach involves encoding CRISPR sequences on either side of an antibiotic resistant gene, which may trigger the gene’s destruction. The genes can potentially be delivered via viruses (called bacteriophages), which in turn can be engineered to target specific bacteria. This precision technology eliminates the issue of accidentally wiping out “friendly” bacteria along with harmful bacteria—a problem seen with many current antibiotics.