Liptin: Novel Antibiotic Compounds

SUPERBUGS: A WORLDWIDE THREAT

The development of antibiotic-resistant (AR) bacteria, or superbugs, is quickly becoming the largest threat to modern medicine, affecting the ability to treat or prevent even the most common types of infections. A growing list of infections, including pneumonia, tuberculosis, blood poisoning, and food-borne diseases, are becoming harder, and in some cases impossible, to treat as current antibiotics become less effective against AR infections. This will lead to higher medical costs, prolonged hospital stays, and ultimately increased mortality rates.

LIMITATIONS & ISSUES WITH CURRENT ANTIBIOTICS

The antibiotics available today are inadequate to prevent and fight infections caused by AR bacteria. Current antibiotics only target a specific site in the bacteria - such as targeting the synthesis of the cell wall, protein, or DNA - to inhibit growth or even kill the bacteria. However, the bacterial genome can always find a way to reroute the antibiotic’s single mode of action, leading to the development of antibiotic resistance.

NOTEWORTHY HISTORICAL IMPACTS

Performing surgery was extremely risky until the discovery of penicillin in the 1940’s. These findings ushered in the era of modern medicine, as the confidence placed in antibiotics allowed for the rapid advancement of numerous surgical techniques and therapies utilized today. However, the emergence of AR bacteria now threatens to push medicine back into the age where common infections and minor injuries
can kill once again.

SOLUTION & ADVANTAGES

Researchers at Wichita State University developed a new class of antibiotic compounds, termed Liptin, which act on bacteria in an entirely new fashion. Initial testing included fi ve of the six ESKAPE pathogens, and show bacteriocidial results. The capabilities of these compounds are advantageous in the following ways:

  • Effective against gram-positive and gram-negative bacteria
  • Liptin compounds bind to plasma membrane and stay bound
  • Binding causes a wave effect across the plasma membrane, disrupting numerous membrane and cellular functions

TARGET:  PLASMA MEMBRANE

The plasma membrane is not only responsible for protecting bacteria from its surroundings, but also participates in a number of processes crucial for cell survival. There are three major phospholipid head groups found within bacterial plasma membranes - and one head group, phosphatidylglycerol (PG), is found in abundance. PG is a favorable target for Liptin to bind to as PG is found in very small amounts in eukaryotes (mammals), and not in the outer leaflet of their cell membranes, hence Liptin’s ability to target only the bacteria, which are prokaryotes.

MECHANISM OF ACTION

A transformation occurs when Liptin binds to PG. The entire PG head group swells in size and its charge changes from negative to positive.This initial step depolarizes the plasma membrane, causing a wave of effects to be sent along the membrane and further alters and disrupts cell functions, homeostasis, and physiochemical properties. With Liptin’s ability to affect multiple functions by binding to PG, its mechanism is advantageous when compared to other antibiotic modes of action that attack a ‘singlefunction’ site. Since Liptin affects multiple functions, the ability for bacteria to generate resistance is expected to be very low.

LIPTIN STRUCTURE

Liptin has a high affinity and selectivity for PG, binding within 20 nanoseconds. The structure of Liptin allows for this, with a three-dimensional binding pocket that is complementary for the PG head group. As Liptin binds to PG, it stays bound and initiates a chain of events to stop bacterial growth.

TESTING & RESULTS

Liptin has a high affinity and selectivity for PG, binding within 20 nanoseconds. The structure of Liptin allows for this, with a three-dimensional binding pocket that is complementary for the PG head group. As Liptin binds to PG, it stays bound and initiates a chain of events to stop bacterial growth.

CELL LINES TESTED

The cell lines tested are a handful of bacterial strains known for their ability to gain antibiotic resistance. The in-vitro testing included five ESKAPE pathogens, which are the leading cause of nosocomial infections throughout the world and responsible for over 23,000 deaths in the US each year.

  • Acinetobacter baumannii*
  • Escherichia coli
  • Enterococcus faecium*
  • Klebsiella pneumoniae*
  • MRSA
  • Mycobacterium smegatis
  • Pseudomonas aerujinosa*
  • Staphylococcus aereus*

INVENTOR

Dr. Dennis Burns is a professor of organic chemistry at Wichita State University. His research involves pharmaceutical drug design, specifically the development and synthessi of new molecultes to combat the emerging threat of drug-resistant bacteria. Dr. Burns has spent the last 14 years developing these Liptin compounds with this research focus in mind. Support and funding for this research endeavor has came from programs such as NSF, NSF EPSCOR, ACS, as well as K-INBRE, a NIH program.

* ESKAPE pathogens


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CONTACT
Gael Tisack
Director, Technology Evaluation & Industry Engagement
316.978.6980

- Patent Pending -