A Screen of Natural Product Extracts Identifies Moenomycin as a Potent Antigonococcal Agent.

Increasing multidrug resistance in Neisseria gonorrheae is a growing public health crisis. Resistance to the last line therapies, cephalosporins and azithromycin, are of particular concern, fueling the need to discover new treatments. Here, we identified the phosphoglycolipid moenomycin from a screen of microbial natural products against drug-resistant N. gonorrheae as a potent antigonococcal agent. Moenomycin demonstrates excellent activity (MIC = 0.004-0.03 μg/mL) against a variety of multidrug-resistant N. gonorrheae. Importantly, moenomycin, thought to be a Gram-positive specific antibiotic, penetrates the Gram-negative gonococcal outer membrane. Moenomycin causes intracellular accumulation of peptidoglycan precursors, cell blebbing, and rupture of the cell envelope, all consistent with cell wall biosynthesis inhibition. Serial bacterial exposure to moenomycin for 14 days revealed slow development of resistance (MICDay14 = 0.03-0.06 μg/mL), unlike the clinically used drug azithromycin. Our results offer the potential utility of moenomycin as a lead for antigonococcal therapeutic candidates and warrant further investigation.

[1]  T. Johnson,et al.  Resistance-Guided Discovery of Elfamycin Antibiotic Producers with Antigonococcal Activity. , 2020, ACS infectious diseases.

[2]  Maxwell Z. Wilson,et al.  A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance , 2020, Cell.

[3]  Gerard D. Wright,et al.  Venturicidin A, A Membrane-active Natural Product Inhibitor of ATP synthase Potentiates Aminoglycoside Antibiotics , 2020, Scientific Reports.

[4]  M. Seleem,et al.  Investigation of auranofin and gold-containing analogues antibacterial activity against multidrug-resistant Neisseria gonorrhoeae , 2020, Scientific Reports.

[5]  Y. Brun,et al.  Evolution-guided discovery of antibiotics that inhibit peptidoglycan remodelling , 2020, Nature.

[6]  T. Haselhorst,et al.  Neisseria gonorrhoeae Becomes Susceptible to Polymyxin B and Colistin in the Presence of PBT2. , 2019, ACS infectious diseases.

[7]  G. Jarvis,et al.  Treatment of human challenge and MDR strains of Neisseria gonorrhoeae with LpxC inhibitors , 2018, The Journal of antimicrobial chemotherapy.

[8]  Li-hua Hu,et al.  Susceptibility of Neisseria gonorrhoeae to azithromycin and ceftriaxone in China: A retrospective study of national surveillance data from 2013 to 2016 , 2018, PLoS medicine.

[9]  M. Surette,et al.  Transformation of the Anticancer Drug Doxorubicin in the Human Gut Microbiome. , 2018, ACS infectious diseases.

[10]  Michelle F. Richter,et al.  Predictive compound accumulation rules yield a broad-spectrum antibiotic , 2017, Nature.

[11]  L. Sánchez-Busó,et al.  The novel 2016 WHO Neisseria gonorrhoeae reference strains for global quality assurance of laboratory investigations: phenotypic, genetic and reference genome characterization. , 2016, The Journal of antimicrobial chemotherapy.

[12]  Andrew J. Lamb,et al.  Morphological and ultrastructural changes in bacterial cells as an indicator of antibacterial mechanism of action , 2016, Cellular and Molecular Life Sciences.

[13]  J. Kalinowski,et al.  A gene cluster for the biosynthesis of moenomycin family antibiotics in the genome of teicoplanin producer Actinoplanes teichomyceticus , 2016, Applied Microbiology and Biotechnology.

[14]  S. Ram,et al.  Immunization against a Saccharide Epitope Accelerates Clearance of Experimental Gonococcal Infection , 2013, PLoS pathogens.

[15]  S. Walker,et al.  Moenomycin family antibiotics: chemical synthesis, biosynthesis, and biological activity. , 2010, Natural product reports.

[16]  S. Normark,et al.  Cell envelope of Neisseria gonorrhoeae. A comparative study with Escherichia coli. , 1976, The British journal of venereal diseases.