Abstract
Summary WAP‐8294A is a group of cyclic lipodepsipeptides and considered as the first‐in‐class new chemical entity with potent activity against methicillin‐resistant Staphylococcus aureus. One of the roadblocks in developing the WAP‐8294A antibiotics is the very low yield in Lysobacter. Here, we carried out a systematic investigation of the nutritional and environmental conditions in an engineered L. enzymogenes strain for the optimal production of WAP‐8294A. We developed an activity‐based simple method for quick screening of various factors, which enabled us to optimize the culture conditions. With the method, we were able to improve the WAP‐8294A yield by 10‐fold in small‐scale cultures and approximately 15‐fold in scale‐up fermentation. Additionally, we found the ratio of WAP‐8294A2 to WAP‐8294A1 in the strains could be manipulated through medium optimization. The development of a practical method for yield improvement in Lysobacter will facilitate the ongoing basic research and clinical studies to develop WAP‐8294A into true therapeutics.
Highlights
The constant emergence of multidrug-resistant bacterial pathogens is a major threat to human health, and nosocomial infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in hospitals have become an especially serious clinical problem
The constant emergence of multidrug-resistant bacterial pathogens is a major threat to human health, and nosocomial infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in hospitals have become an Received 30 April, 2019; revised 2 August, 2019; accepted 13 August, 2019. *For correspondence
We carried out a systematic investigation of nutritional and environmental conditions in an engineered L. enzymogenes strain (OH11-MHSAF, in which the key biosynthetic gene for the main metabolite HSAF in L. enzymogenes has been deleted) for optimal production of WAP-8294A
Summary
The constant emergence of multidrug-resistant bacterial pathogens is a major threat to human health, and nosocomial infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in hospitals have become an especially serious clinical problem. Vancomycin serves as the cornerstone of the treatment of these drug-resistant Gram-positive infections in the past several decades, which is regarded as a last resort in treating MRSA infections. Several new drugs, such as daptomycin, telavancin and ceftaroline, have been approved for the treatment of infections caused by drug-resistant Gram-positive pathogens (Choo and Chambers, 2016). The occurrence of drug resistance to these antibiotics is not a question of if but when, and there have been reports on MRSA resistant to daptomycin and telavancin (Nigo et al, 2017; Roch et al, 2017). The discovery of new antibiotics is an urgent and continual need for human health
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