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Model showing the membrane action of octapeptin antibiotics compared to polymyxin antibiotics.

Octapeptins

With multi drug resistant (MDR) gram negative bacterial infections including Pseudomonas aeruginosa and Acinetobacter baumannii on the rise, The World Health Organization has deemed them one of three of the largest threats to public health.As a last line of defense, polymyxin b antibiotics are typically employed against these gram negative “superbugs.” However, the emergence of resistance to these last resort antibiotics have been shown in multiple MDR pathogens. For this reason, it is urgent that new solutions are explored to combat these mutants with resistance to these drugs. Octapeptin is a peptide antibiotic that is being investigated to treat infections arising from gram negative bacteria that have become resistant to the antibiotics that are currently used. It was originally isolated from Bacillus circulans and is effective in disrupting bacterial membranes. A novel characteristic and one that is essential in the action of octapeptin on bacterial membranes is a covalently linked fatty acid that is attached to the peptide itself. Other treatments centered on disrupting the plasma membrane of microorganisms have been pursued, but have shown to be toxic to host cells, or have become obsolete due to bacterial resistance. Octapeptin is of great interest because it is novel to bacteria and due to its ability to disrupt bacterial membranes while remaining relatively non-toxic to the host. Further, unlike polymyxin antibiotics, it retains activity against gram positive bacterial infections, can also treat fungal infections, and most importantly, has been shown to disrupt polymyxin resistant gram negative bacteria as well.

Resistance:

The evolution of bacterial pathogens has resulted in the obsolescence of various antimicrobials used to treat infection. Moreover, many bacteria strains are multidrug-resistant to several antibiotics making them severely difficult to treat. Further, the last line of defense in treating bacterial infections attributed to the polymyxin drugs, namely colistin are now futile in treating various bacterial infections. Bacterial targets can gain resistance through enzyme modification, through ribosomal proteins that confer resistance or through population dynamics such as the secretion of exopolysaccharides. The deaths related to multidrug-resistant bacterial infections have increased in the modern era. The economic impact of this type of resistance is also astronomical.

Modern anti-resistance strategies:

The discovery of the first three antibiotics including Penicillin, resulted in a fruitful discovery period of novel antibiotics beginning in the 1950s and extending through the 1970s. Since this coined “golden era,” there have not been any new discoveries. The modern approach to fighting antibiotic resistance of emerging and re-emerging pathogens, is to draw on existing antibiotics that were already discovered. Like many antibiotics developed in the golden era, octapeptin was discovered, then discontinued during this time due to the rapid influx of novel antibiotics that were selected over it. With the state of antibiotic resistance and the “superbugs”, new research is being pursued to determine the effectiveness of octapeptin in treating bacterial infections.

Chemical Structure:

With structures similar to polymyxin, octapeptin contain the same heptapeptide core as are found in polymyxin lipodecapeptides. Further, more similarities are noted between the two when looking at the cationic diaminabutyric acid (DAB) residues within the heptapeptide core which are observed to be at the same positions for both drugs. Both drugs are cyclic cationic peptide drugs with an amide bond facilitating their cyclic nature. However, there are some differences that include:

1) The substitution of a leucine residue that replaces threonine at the corresponding position on polymyxin.

2) The replacement L-Dab with D-Dab at one of the positions on octapeptin.

3) The presence of N-terminal 3(R)-hydroxy fatty acids contrasting the mixture of alkyl fatty acids found in polymyxins.

Model of the cyclic chemical structure of octapeptin.

Mode of action:

The center of focus regarding the use of octapeptin is in treating polymyxin-resistant gram negative bacteria. The electrostatic dependency of the interaction of polymyxin and lipid A of bacterial membranes has eliminated the effectiveness of polymyxin on modified gram negative bacteria that have altered the state of their membrane to limit this electrostatic interaction. Octapeptin is very similar structurally to polymyxin, but differs in its mode of action, which does not depend on an electrostatic interaction with lipid A. This key feature has counteracted the modifications on the membranes of polymyxin resistant gram negative bacteria. Octapeptin attacks the outer membrane, beginning with a polar interaction between lipid A as well as phospholipid head groups. After this initial interaction with the membrane, octapeptin inserts itself into the fatty acyl core of the outer membrane and embeds itself in the membrane. This stepwise action of octapeptin that differs slightly from polymyxin, allows it to effectively disrupt the membranes of the polymyxin resistant bacteria.