AFN-1252 in vitro absorption studies and pharmacokinetics following microdosing in healthy subjects

Journal of Biological Chemistry

Rock

2015

104

Bacterial type II fatty acid synthesis (FASII) is a target for the development of novel therapeutics. Bacteria incorporate extracellular fatty acids into membrane lipids, raising the question of whether pathogens use host fatty acids to bypass FASII and defeat FASII therapeutics. Some pathogens suppress FASII when exogenous fatty acids are present to bypass FASII therapeutics. FASII inhibition cannot be bypassed in many bacteria because essential fatty acids cannot be obtained from the host. FASII antibiotics may not be effective against all bacteria, but a broad spectrum of Gram-negative and -positive pathogens can be effectively treated with FASII inhibitors. The Biological ProblemThe discovery of antibiotics for the treatment of infectious bacterial diseases has led to significant improvements in human health. The success of these broad-spectrum "miracle drugs" is reflected in the dearth of new antibiotic classes introduced in the last 30 years (1). However, the steady increase in bacterial antibiotic resistance to all antimicrobials in clinical use (2, 3) has caused infectious bacterial diseases to re-emerge as a serious threat to human health. These resistant bacteria are a clear and present danger that will require the discovery of new antibiotic targets and drugs to combat (4). Fatty acid synthesis is a vital facet of bacterial physiology, and its essentiality for membrane formation makes it an attractive target for drug discovery (5). Nature has exploited this dependence to produce a variety of natural products that target bacterial fatty acid synthesis (5-7). Selective targeting of the bacterial pathway is possible due to the significant differences in the structure of eukaryotic and bacterial fatty acid synthesis systems. Mammalian type I fatty acid synthase is a large, multifunctional peptide that elongates acetyl-CoA to produce a single product, palmitic acid (8).In the bacterial type II system (FASII), 2 each enzymatic step is carried out by a discrete, monofunctional enzyme ( Fig. 1) (9).Many inhibitors targeting FASII enzymes have been made in the past two decades, and several of these inhibitors are effective antibiotics both in vitro and in animal models (10 -13). Two of these compounds, AFN-1252 and CG400549, have proven efficacy in human clinical trials, providing direct evidence that targeting FASII components can result in effective therapeutic agents (14,15).Most bacteria are able to incorporate extracellular fatty acids into their membrane phospholipids, leading to the important question of whether this property will allow them to circumvent FASII inhibitors by acquiring the fatty acids they need from the host. Brinster et al. (16) argued that FASII is not an antibacterial target in Gram-positive bacteria due to the ability of Streptococcus agalactiae to circumvent FASII inhibitors when supplied with exogenous host-derived fatty acids. However, the situation is more complex because not all Gram-positive bacteria have the same fatty acid structures as mammals, and the conclusion is not co...

Section: (9)mentioning

confidence: 99%

How Bacterial Pathogens Eat Host Lipids: Implications for the Development of Fatty Acid Synthesis Therapeutics

Journal of Biological Chemistry

Rock

2015

104

“…Thus, AFN-1252 is a sharp tool to study the effects of FASII inhibition on C. trachomatis replication in light of its selectivity, its binding affinity, and the absence of off-target effects on human cells (11,36).…”

Section: ⅐Afn-1252 Complex These Data Indicated That Afn-1252 Inhibitedmentioning

confidence: 99%

“…Thus, one function of FASII would be to provide these 3-hydroxy fatty acids for LOS synthesis in C. trachomatis, but it is unknown whether FASII is needed for phospholipid synthesis. We used AFN-1252 as a chemical biology tool to specifically inhibit the enoyl-acyl carrier protein (ACP) reductase (FabI) (11)(12)(13) and assess the role of FASII in C. trachomatis replication. C. trachomatis is predicted to encode a FASII system that depends on FabI (Fig.…”

mentioning

confidence: 99%

Type II Fatty Acid Synthesis Is Essential for the Replication of Chlamydia trachomatis

Journal of Biological Chemistry

AbdelRahman

Robertson

et al. 2014

Background: Chlamydia trachomatis has a phospholipid composition that resembles its eukaryotic host, but it contains branched-chain fatty acids of chlamydial origin. Results: The inhibition of the enoyl-acyl carrier protein reductase (FabI) in chlamydial fatty acid synthesis blocks C. trachomatis replication. Conclusion: Bacterial FASII is required for C. trachomatis proliferation. Significance: FabI is a therapeutic target against C. trachomatis.

“…1), is an example of a FabI inhibitor with the properties of a pathogen-selective antibiotic based on both target distribution and isozyme selectivity (17). Debio 1452 is specifically designed to target staphylococcal FabI, a key component of bacterial fatty acid synthesis (18)(19)(20). FabI is essential in Staphylococcus species (11) but is not found in many other groups of bacteria.…”

mentioning

confidence: 99%

A Pathogen-Selective Antibiotic Minimizes Disturbance to the Microbiome

Antimicrob Agents Chemother

Carter

Vuagniaux

et al. 2016

c Broad-spectrum antibiotic therapy decimates the gut microbiome, resulting in a variety of negative health consequences. Debio 1452 is a staphylococcus-selective enoyl-acyl carrier protein reductase (FabI) inhibitor under clinical development and was used to determine whether treatment with pathogen-selective antibiotics would minimize disturbance to the microbiome. The effect of oral Debio 1452 on the microbiota of mice was compared to the effects of four commonly used broad-spectrum oral antibiotics. During the 10 days of oral Debio 1452 treatment, there was minimal disturbance to the gut bacterial abundance and composition, with only the unclassified S24-7 taxon reduced at days 6 and 10. In comparison, broad-spectrum oral antibiotics caused ϳ100-to 4,000-fold decreases in gut bacterial abundance and severely altered the microbial composition. The gut bacterial abundance and composition of Debio 1452-treated mice were indistinguishable from those of untreated mice 2 days after the antibiotic treatment was stopped. In contrast, the bacterial abundance in broad-spectrum-antibiotic-treated mice took up to 7 days to recover, and the gut composition of the broad-spectrum-antibiotic-treated mice remained different from that of the control group 20 days after the cessation of antibiotic treatment. These results illustrate that a pathogen-selective approach to antibiotic development will minimize disturbance to the gut microbiome.