SIGA Pharmaceuticals, Inc. (Nasdaq: SGPH) is a bioscience company committed to the discovery and development of novel products for the prevention and treatment of a wide variety of infectious diseases. SIGA has developed a broadly applicable technology platform for developing vaccines and antibiotics which is based on the company's pioneering research into the structure, function and processing of bacterial surface proteins - the proteins pathogens use to bind to and infect human tissues.


Anti-infectives Overview

SIGA's antibiotic program targets the growing problem of drug-resistant bacteria. SIGA's unique antibiotic development approach focuses on disarming bacteria by interfering with their ability to attach to and colonize human tissue, required steps in initiating and maintaining an infection. This methodology addresses the problem of antibiotic resistance in two ways. First, no existing class of antibiotics works through this or a similar mechanism, so that bacteria resistant to currently available antibiotics would not be resistant to this new class. Second, by rendering bacteria innocuous rather than killing them, SIGA's approach should be less likely to lead to antibiotic resistance in the first place. SIGA's partnership with Wyeth-Ayerst validates this approach to the development of a new class of antibiotics.

Gram-positive

Gram-positive bacterial pathogens pose a major threat to human health due to the development of resistance to most clinically relevant antibiotics. This is particularly true with Staphylococcus aureus, a major source of nosocomial infections as well as a leading cause of life threatening systemic maladies such as septicemia and meningitis. Staphylococci are also a leading cause of cutaneous infections, opportunistic infections and infections of the urinary tract. Furthermore, it is estimated that as high as 65% of all infections of prosthetic devices, catheters and shunts are caused by S. epidermidis. Ninety-five percent of clinical isolates of S. aureus are penicillin resistant while methicillin resistance (MRSA) is estimated at 50% of hospital isolates. The most alarming trend is the appearance of vancomycin resistant S. aureus and Enterococcus faecalis. Vancomycin represents the antibiotic of last resort in the clinic. Antibiotic resistance in the streptococci is a growing problem as well, with >30% of S. pneumoniae resistant to penicillin. Streptococcus pneumoniae is a leading cause of bacterial pneumonia, causing 500,000 cases in US annually, as well as meningitis, otitis media, sinusitis and bacteremia. Erythromycin resistance is a critical issue with Streptococcus pyogenes, which causes strep throat. Resistance to this and other macrolides ranged from 15 to 30 % of clinical isolates from various countries.

SIGA is developing a new class of therapeutics for the treatment of Gram-positive infections. SIGA's founding scientists have discovered and characterized a novel pathway for the secretion and anchoring of cell wall proteins on the surface of Gram-positive organisms. The mechanism is conserved in all clinically relevant Gram-positive organisms and is responsible for the surface anchoring of over 80 cell surface proteins. Surface proteins, such as M protein and fibronectin-binding protein (FBP), are critical for tissue adherence and colonization, while protein A and IgA binding protein are critical for eluding or modifying the host immune response. These activities are essential for the invading organisms to initiate the infectious process and persist in the host. It has been demonstrated in many independent laboratories that blocking these activities allows the host to repel the invading organism. SIGA scientists have harnessed this novel pathway and have developed High-Throughput Screening assays for the identification of novel small-molecule inhibitors of this pathway.

The worldwide annual market for antibiotics is estimated at nearly $22 billion. There are 25 million reported cases of "strep throat" annually in the U.S which results in a treatment cost of nearly $1 billion, while the cost alone of dealing with antibiotic resistance is estimated at $100 million annually. A novel therapeutic that will effectively clear a wide range of Gram-positive pathogens is expected to make a significant impact in this market. Our novel anti-infectives are anticipated to be effective against antibiotic resistance strains as they will block the adherence of organisms to tissue; working at a completely novel step in the pathogenesis pathway. Furthermore, our approach is not expected to apply strong selection pressure for the development of resistant organisms, as the drugs are not expected to be bactericidal.

 

Gram-negative

In response to the rapidly rising incidence of antibiotic resistance in many Gram-negative pathogens, pharmaceutical interests, large and small, are seeking new intervention strategies. The trend, however, is to re-engineer existing agents and to focus on targets that were successful in the past, finding temporary fixes circumventing the resistance mechanism put forth by the microbe. SIGA has chosen a new path. We are developing a new family of anti-infectives that will disarm pathogens by blocking the assembly of the bacterial pilus. Pilus biogenesis is essential for bacterial pathogenesis, since the initial interaction between the pathogen and host occurs via the pilus. For example, pyelonephritogenic strains of Escherichia coli must gain a "foothold" in the urinary tract in order to cause disease. Colonization of both the bladder and the kidney initiates with a specific adherence event between an adhesin molecule localized to the tip of the bacterial pilus, and a specific receptor, typically a sugar moiety, expressed on the uroepithelium. Pyelonephritic strains of E. coli that express pili lacking the adhesive component are incapable of causing pyelonephritis in monkeys. Similarly, cystitis isolates of E. coli that assemble adhesin minus pili are avirulent in mice. These findings highlight an assembly pathway that has not, until now, been the focus of a concentrated research program for the development of novel anti-infectives.

The pilus biogenesis pathway is conserved throughout the Enterobacteriaceae and in virtually all Gram-negative bacteria; therefore, the development of potent anti-infectives has the potential to bring to market a generalized treatment protocol for many Gram-negative pathogens. Members of the Enterobacteriaceae family are responsible for 30-35% of all septicemia cases and 70% of all urinary tract infections (UTI). Treatment of cystitis and pyelonephritis alone is a $1 billion annual market. Nosocomial infections such as bacteremia, surgical wound infections, pneumonia and also UTI affect 5% of all hospitalized patients at an annual cost of $2 billion per year. It is estimated that the annual market for antibiotic treatment of bacterial disease, including pneumonia, inner ear infection, gastroenteritis, cystitis and pyelonephritis caused by Gram-negative bacteria could reach $22 billion. SIGA's novel anti-infective technology is expected to have a significant impact on this market.

SIGA has optimized a High-Throughput Screening (HTS) assay based on the activity of an enzyme essential to the pilus-biogenesis process. The enzyme is referred to as a periplasmic chaperone and is conserved throughout the Enterobacteriaceae family. SIGA scientists have also developed a series of secondary and tertiary screens that will be implemented to analyze and validate lead compounds that arise from HTS. In addition to High-Throughput Screening, SIGA has access to structural information that will assist structure-based drug design and combinatorial chemistry to rapidly optimize novel drug candidates.

Broad Spectrum

The rise of bacterial strains resistant to multiple antibiotics poses a major threat to human health and is one of the most pressing problems facing the medical community today. The current situation with Escherichia coli serves as a good example of this dangerous trend in Gram-negative pathogens. Thirty percent of E. coli isolates from the general community and 40-50% of isolates from hospital and elder care settings are resistant to amoxicillin. In geriatric care centers some 40% of E. coli strains isolated from urine are resistant to trimethoprim-sulfamethoxazole (TMP-SMX). This is very disturbing, since TMP-SMX is the drug of choice for treatment of urinary tract infections (UTI). UTI is also the most common cause of nosocomial infections, 42% of all hospital acquired infections, and the most common source of bacteremia in community health setting, this represents a $1-2 billion per year problem. On the Gram-positive side, 95% of clinical isolates of S. aureus are penicillin resistant while methicillin resistance (MRSA) is estimated at 50% of hospital isolates. The most alarming trend is the appearance of vancomycin resistant S. aureus and Enterococcus faecalis. Vancomycin represents the antibiotic of last resort in the clinic for treatment of infections caused by these pathogens. Antibiotic resistance in the streptococci is a growing problem as well, with >30% of S. pneumoniae isolates resistant to penicillin. Streptococcus pneumoniae is a leading cause of bacterial pneumonia, causing 500,000 cases in US annually, as well as meningitis, otitis media, sinusitis and bacteremia. Erythromycin resistance is a critical issue with Streptococcus pyogenes, which causes strep throat. Resistance to this and other macrolides ranged from 15 to 30 % of clinical isolates from various countries. The worldwide annual market for antibiotics is estimated at nearly $22 billion, while the cost alone of dealing with antibiotic resistance is estimated at $100 million annually.

An initial host response to pathogen invasion is the release of oxygen radicals, such as superoxide anions and hydrogen peroxide. The DegP protease is a first-line defense against these toxic compounds, which are lethal to invading pathogens, and is a demonstrated virulence factor for several important pathogens: Salmonella typhimurium, Salmonella typhi, Brucella melitensis and Yersinia enterocolitica. In all of these pathogens it was demonstrated that organisms lacking a functional DegP protease were compromised for virulence and showed an increased sensitivity to oxidative stress. It was also recently demonstrated that in Pseudomonas aeruginosa conversion to mucoidy, the so-called CF phenotype involves two DegP homologues.

Scientists at SIGA recently demonstrated that the DegP protease is conserved in most important Gram-positive pathogens, including S. pyogenes, S. pneumoniae, S. mutans and S. aureus. Moreover, SIGA investigators have shown a conservation of function of this important protease in Gram-positive pathogens and believe that DegP represents a true broad-spectrum anti-infective development target. SIGA research has uncovered a virulence-associated target of the DegP protease that will be utilized to design an assay for High-Throughput Screening for the rapid identification of lead inhibitors of this important anti-infective target.