Bacterial resistance to antibiotics has been an evolving problem since the dawn of the antibiotics era. Isolates of Gram-negative bacteria (GNB) exist that are resistant to nearly all approved antibiotics, and these pathogens are rapidly spreading across the country and across the globe. At the same time, the pipeline of new antibiotics is nearly empty. By contrast to Gram-positive bacteria, Gram-negative organisms protect themselves with an additional outer bilayer membrane. The barrier function of this outer membrane relies on lipopolysaccharide (LPS, or endotoxin), the predominant lipid moiety on the cell surface. Agents that inhibit the synthesis of LPS, such as inhibitors of the enzyme LpxC, are rapidly bactericidal. Indeed, Achaogen has developed an LpxC inhibitor, ACHN-975, that was the first agent in its class to enter Phase I clinical trials. The research program that led to the advancement of ACHN-975 into clinical trials started with a known LpxC inhibitor, CHIR-090. Achaogen then used our deep knowledge of medicinal chemistry rules for synthesizing agents that cross both Gram-negative membranes, and our extensive microbiology capabilities to design, synthesize and test new analogs with improved activity. To further exploit the LPS synthesis pathway, we are examining the enzyme AccC otherwise known as biotin carboxylase. This enzyme catalyzes an early step in Type-II fatty-acid synthesis. Gram-negative bacteria require this enzyme to synthesize the ?-hydroxy lipids that are unique to LPS. As there are no environmental sources of ?-hydroxy fatty acids (by contrast to saturated fatty acids), inhibition of AccC will result in rapid cell death. Inhibitors of purified AccC from Gram-negative bacteria have been published in the literature, and the binding mode of these compounds to the enzyme is well understood through a large number of publicly available co-crystal structures. However, these leads are only weakly active against pathogenic GNB. We believe that we understand the properties of these compounds that prevent their activity in wild-type GNB. Achaogen will again use our deep understanding of medicinal chemistry in the Gram-negative space and our microbiology capabilities to design, synthesize and test new AccC inhibitors with improved properties that will be more active against pathogenic GNB. The successful outcome of this project will be a series of drug-like molecules that are potent inhibitors of purified AccC and have antimicrobial activity against wild-type GNB with MIC's in the range of ? 0.5 ug/mL. Achievement of these goals will allow us to initiate a full scale drug development program.

Public Health Relevance

Gram-negative bacterial infections have become an urgent threat to public health. For example, strains of Klebsiella pneumoniae have been isolated from patients in the United States that are resistant to ALL approved antibiotics. To combat this threat, we must introduce antibiotics that function through entirely new mechanisms, rather than continue to modify existing classes of approved drugs. This project will apply modern methods of drug discovery to create new inhibitors of an essential bacterial enzyme, that is not currently targeted by approved antibiotics.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
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Xu, Zuoyu
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Achaogen, Inc.
South San Francisco
United States
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