A comprehensive regulatory framework to address the unmet need for new antibacterial treatments

Rex, John H.; Eisenstein, Barry I.; Alder, Jeff; Goldberger, Mark; Meyer, Robert; Dane, Aaron; Friedland, Ian R.; Knirsch, Charles; Sanhai, Wendy R.; Tomayko, John F.; Lancaster, Cindy; Jackson, Jennifer

doi:10.1016/s1473-3099(12)70293-1

Cited by 117 publications

(92 citation statements)

References 20 publications

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“…Further discussion showed that the agency also understands that development for traditional indications such as pneumonia also needs "rebooting." Their thoughts on the reboot follow the recommendations of a working group from the pharmaceutical industry (2). How and why did we get here?…”

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confidence: 95%

The FDA Reboot of Antibiotic Development

Shlaes¹,

Sahm

Opiela

et al. 2013

Antimicrob Agents Chemother

127

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mentioning

confidence: 95%

The FDA Reboot of Antibiotic Development

Shlaes¹,

Sahm

Opiela

et al. 2013

Antimicrob Agents Chemother

127

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“…However, with the rise of infections caused by multidrug-resistant bacteria, there is a widely recognized need for new antibacterial compounds (1)(2)(3). The bacterial cell wall is an excellent target for development of antibiotics, because its synthesis is conserved across bacterial pathogens and absent from mammalian cells.…”

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confidence: 99%

Novel Antibacterial Targets and Compounds Revealed by a High-Throughput Cell Wall Reporter Assay

et al. 2015

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A high-throughput phenotypic screen based on a Citrobacter freundii AmpC reporter expressed in Escherichia coli was executed to discover novel inhibitors of bacterial cell wall synthesis, an attractive, well-validated target for antibiotic intervention. Here we describe the discovery and characterization of sulfonyl piperazine and pyrazole compounds, each with novel mechanisms of action. E. coli mutants resistant to these compounds display no cross-resistance to antibiotics of other classes. Resistance to the sulfonyl piperazine maps to LpxH, which catalyzes the fourth step in the synthesis of lipid A, the outer membrane anchor of lipopolysaccharide (LPS). To our knowledge, this compound is the first reported inhibitor of LpxH. Resistance to the pyrazole compound mapped to mutations in either LolC or LolE, components of the essential LolCDE transporter complex, which is required for trafficking of lipoproteins to the outer membrane. Biochemical experiments with E. coli spheroplasts showed that the pyrazole compound is capable of inhibiting the release of lipoproteins from the inner membrane. Both of these compounds have significant promise as chemical probes to further interrogate the potential of these novel cell wall components for antimicrobial therapy. IMPORTANCEThe prevalence of antibacterial resistance, particularly among Gram-negative organisms, signals a need for novel antibacterial agents. A phenotypic screen using AmpC as a sensor for compounds that inhibit processes involved in Gram-negative envelope biogenesis led to the identification of two novel inhibitors with unique mechanisms of action targeting Escherichia coli outer membrane biogenesis. One compound inhibits the transport system for lipoprotein transport to the outer membrane, while the other compound inhibits synthesis of lipopolysaccharide. These results indicate that it is still possible to uncover new compounds with intrinsic antibacterial activity that inhibit novel targets related to the cell envelope, suggesting that the Gram-negative cell envelope still has untapped potential for therapeutic intervention.

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“…Infections caused by multidrug-resistant Gram-negative bacteria are a growing threat to human health, and there is an urgent need for new antibacterial agents (6)(7)(8). All five of the proteins that comprise the Lol system have been shown to be essential for growth of Escherichia coli and are well conserved across the gammaproteobacteria (3,(9)(10)(11).…”

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confidence: 99%

Small-Molecule Inhibitors of Gram-Negative Lipoprotein Trafficking Discovered by Phenotypic Screening

et al. 2015

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cIn Gram-negative bacteria, lipoproteins are transported to the outer membrane by the Lol system. In this process, lipoproteins are released from the inner membrane by the ABC transporter LolCDE and passed to LolA, a diffusible periplasmic molecular chaperone. Lipoproteins are then transferred to the outer membrane receptor protein, LolB, for insertion in the outer membrane. Here we describe the discovery and characterization of novel pyridineimidazole compounds that inhibit this process. Escherichia coli mutants resistant to the pyridineimidazoles show no cross-resistance to other classes of antibiotics and map to either the LolC or LolE protein of the LolCDE transporter complex. The pyridineimidazoles were shown to inhibit the LolA-dependent release of the lipoprotein Lpp from E. coli spheroplasts. These results combined with bacterial cytological profiling are consistent with LolCDE-mediated disruption of lipoprotein targeting to the outer membrane as the mode of action of these pyridineimidazoles. The pyridineimidazoles are the first reported inhibitors of the LolCDE complex, a target which has never been exploited for therapeutic intervention. These compounds open the door to further interrogation of the outer membrane lipoprotein transport pathway as a target for antimicrobial therapy.T he most distinguishing feature of Gram-negative bacteria is their cell envelope, which is comprised of both an inner and an outer membrane bilayer. The outer membrane has a unique composition of lipoproteins, ␤-barrel proteins, lipopolysaccharides, and phospholipids. Lipoproteins, membrane proteins that are covalently modified with lipids, are involved in a variety of integral cellular functions, such as the synthesis and maintenance of the cell surface and the transport of substrates (reviewed in reference 1). Lipoproteins are synthesized as precursors in the cytoplasm. Upon transit across the inner membrane by either the Sec or Tat machinery, the export signal peptide is cleaved, and attached to its amino terminus is a lipid moiety. This lipid serves as a membrane anchor for the lipoprotein. Some lipoproteins remain in the outer leaflet of the inner membrane, while others must cross the hydrophilic periplasmic space to the outer membrane. This sorting of lipoproteins to the outer membrane is achieved by the Lol system, which consists of five proteins (Fig. 1) (reviewed in reference 1). In this process, lipoproteins destined for the outer membrane are released from the inner membrane by the LolCDE complex, an inner membrane ABC transporter. LolCDE transfers the lipoproteins to LolA, a diffusible periplasmic chaperone (2, 3). LolA then transfers the lipoprotein to LolB, the outer membrane lipoprotein receptor, which incorporates these lipoproteins into the inner leaflet of the outer membrane (1, 4). This is in contrast to Grampositive bacteria, which have a single membrane bilayer; therefore, localization of lipoproteins to the cell surface requires only export through the cytoplasmic membrane and acylation (5).Infections c...

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A comprehensive regulatory framework to address the unmet need for new antibacterial treatments

Cited by 117 publications

References 20 publications

The FDA Reboot of Antibiotic Development

The FDA Reboot of Antibiotic Development

Novel Antibacterial Targets and Compounds Revealed by a High-Throughput Cell Wall Reporter Assay

Small-Molecule Inhibitors of Gram-Negative Lipoprotein Trafficking Discovered by Phenotypic Screening

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