ANTIBACTERIALS STARTUPS WITH DRUGS TARGETING GRAM-NEVAGIVE BACTERIA AND INFECTIONS DRAW SERIOUS VENTURE CAPITAL

 Salmonella Bacteria a part of the proteobacteria class bateria which is Gram-negative bacterria 

Bacterial resistance to antibiotics is a growing problem, particularly for hospitals. Of particular concern for hospitals are Gram-negative bacteria, which have a two-layered cell wall that makes them especially resistant to existing drugs.

As a result, start-ups with potential treatments for Gram-negative infections are now hot targets for venture investors and corporate acquirers.

Among them is Rampex Pharmaceuticals, a San Diego-based startup which VentureWire reports has now raised up to $76 million in venture capital for a novel approach to fighting the problem.

Rampex Pharmaceuticals hasn’t said how its internally discovered drugs work or whether or not they fall into an existing class of antibiotics. But Chief Executive Daniel Burgess said his company’s drugs will be effective against multiple Gram-negative bacteria that now escape the effects of today’s antibacterials. Various types of drugs, such as beta lactams, aminoglycosides and fluoroquinolones, are now used against Gram-negative bacteria, but resistance is a problem for antibiotics in each class, according to Burgess.

The conditions Rampex could target include intra-abdominal infections and complicated urinary-tract infections, he said. The company said it expects to file for U.S. approval for its first product in the second half of 2012 and to seek approval to begin clinical studies of its second drug early next year, but Burgess didn’t give further details.

A 2009 Centers for Disease Control and Prevention report said the overall annual direct-medical costs of hospital-acquired infection in U.S. hospitals ranges from $28.4 billion to $33.8 billion and $35.7 billion to $45 billion, depending on the Consumer Price Index adjustments used to account for the rate of inflation in hospital resource prices.

Seeing opportunity in this problem, pharmaceutical companies are showing more interest in antibiotics after years of favoring drugs for chronic problems. Last year, for example, an anti-infectives spinout from Sanofi, Novexel, was acquired by AstraZeneca in a $505 million deal.

In late 2009, Cubist Pharmaceuticals acquired venture-funded Calixa Therapeutics to secure access to an intravenous therapy for certain Gram-negative infections in the hospital. Meanwhile, private drug companies in this field such as Achaogen and Tetraphase Pharmaceuticals have raised large venture rounds.

COMMENTARY:  With annual sales of over $26 billion, antibiotics represent one of the largest therapeutic categories from a revenue perspective. Each year, almost 2 million Americans develop hospital-acquired infections such as sepsis and pneumonia, and over 95,000 of those infections resulting in patient death.  The growing problem of drug-resistant bacteria will continue to drive growth in new and expanding market opportunities. 

Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain (commonly  safranin) is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color. The test itself is useful in classifying two distinct types of bacteria based on the structural differences of their bacterial cell walls. Gram-positive bacteria will retain the crystal violet dye when washed in a decolorizing solution.

Cell structure of Gram-negative (left) and Gram-positive (right) bacteria

The pathogenic capability of Gram-negative bacteria is often associated with certain components of Gram-negative cell walls, in particular, the lipopolysaccharide layer (also known as LPS or endotoxin layer). In humans, LPS triggers an innate immune response characterized by cytokine production and immune system activation.  Inflammation is a common result of cytokine (from the Greek cyto, cell and kinesis, movement) production, which can also produce host toxicity.

The following characteristics are displayed by Gram-negative bacteria:

1. Cytoplasmic membrane
2. Thin peptidoglycan layer (which is much thinner than in Gram-positive bacteria)
3. Outer membrane containing lipopolysaccharide (LPS, which consists of lipid A, core polysaccharide, and O antigen) outside the peptidoglycan layer
4. Porins exist in the outer membrane, which act like pores for particular molecules
5. There is a space between the layers of peptidoglycan and the secondary cell membrane called the periplasmic space
6. The S-layer is directly attached to the outer membrane, rather than the peptidoglycan
7. If present, flagella have four supporting rings instead of two
8. No teichoic acids or lipoteichoic acids are present
9. Lipoproteins are attached to the polysaccharide backbone.
10. Most of them contain Braun's lipoprotein, which serves as a link between the outer membrane and the peptidoglycan chain by a covalent bound
11. Most do not sporulate (Coxiella burnetii, which produces spore-like structures, is a notable exception)

Gram-negative bacterial infection refers to a disease caused by Gram-negative bacteria. One example is E. coli.

Click Image To Enlarge

It is important to recognize that this class is defined morphologically (by the presence of a bacterial outer membrane), and not histologically (by a pink appearance when stained), though the two usually coincide.

There are many groups of Gram negative bacteria such as

• Cyanobacteria
  
• Spirochaetes
  
• Green Sulphur 
  
• Green Non-Sulphur Bacteria
  
• Proteobacteria is one of the major groups of known Gram negative bacteria and includes bacteria like: 
  • E.Coli 
  • Salmonella 
  • Pseudomonas 
  • Moraxella 
  • Helicobacter 
  • Stenotrophomonas 
  • Legionella  (causes Pontiac fever and Legionnaires’ disease)
  • Acetic Acid Bacteria

Salmonella Bacteroa

Along with the bacteria mentioned above, there are several other types of Gram negative bacteria such as: 

• Haemophilus influenzae( also known as Bacillus influenzae)
• Neisseria meningitidis  
• Moraxella catarrhalis
• Neisseria gonorrhoeae
• Acinetobacter baumanii (which comes under Nosocomial Gram negative bacterial group).

One reason for this division is that the outer membrane is of major clinical significance: it can play a role in the reduced effectiveness of certain antibiotics, and it is the source of edotoxemia in which endotoxin (a toxic substance associated with bacterial cell wall or core) comes in contact with bloodstreams and gets mixed with blood. Once the endotoxin is mixed in blood, it becomes very hard to stop the toxic substance from harming/destroying healthy tissues and also causing inflammation of the tissues. The substance can reach any part of the body and start to harm the tissues. The Gram negative bacteria can be killed using medication but the endotoxin is very hard to clean from the blood.

The gram status of some organisms is complex or disputed:

• Mycoplasma are sometimes considered gram negative, but because of its lack of a cell wall and unusual membrane composition, it is sometimes considered separately from other gram negative bacteria.
• Gardnerella is often considered gram negative, but it is classified in MeSH as both gram positive and gram negative. It has some traits of gram positive bacteria, but has a gram negative appearance. It has been described as a "gram-variable rod".

Courtesy of an article dated November 10, 2011 appearing in The Wall Street Journal's Venture Capital Dispatch