Micrococcin P2 Targets Clostridioides difficile

Abstract

Clostridioides dif ficile infection is a global public health threat. Extensive in vitro assays using clinical isolates have identified micrococcin P2 (MP2, 1) as a particularly effective anti-C. diff icile agent. MP2 possesses a mode of action that differs from other antibiotics and pharmacokinetic properties that render it especially promising. Its time−kill studies have been investigated using hypervirulent C. dif f icile ribotype 027. DSS (dextran sulfate sodium)-induced in vivo mouse studies with that strain indicate that 1 is better than vancomycin and fidaxomicin. Thus, micrococcin P2 is a valuable platform to be exploited for the development of new anti-C. dif f icile antibiotics.Clostridioides dif f icile is a Gram-positive, spore-forming, toxinproducing, anaerobic bacteria that is becoming a serious health threat. 1 The organism causes severe diarrhea with lifethreatening complications, 2 such as toxic megacolon, pseudomembranous colitis, and systemic inflammatory response syndrome. 3 The prevalence of the hypervirulent strain of C. diff icile PCR ribotype 027 4 adds additional clinical concerns due to its severe disease presentation. C. dif ficile is thus designated as an urgent threat by the U.S. Centers for Disease Control and Prevention (CDC). 5 In the U.S. alone, more than 220 000 cases of C. diff icile infection (CDI), with 12 800 deaths, were reported in 2019. In South Korea, the estimated CDI rate is as high as in the U.S., but the lack of national-level support for antimicrobial stewardship undermines public awareness. 6 Currently, only two antibiotics, vancomycin and fidaxomicin, are approved by the FDA for the treatment of CDI. 7 However, vancomycin suffers from high rates of relapse (25% to 30%), 8 and its broad antibiotic spectrum against Gram-positive bacteria leads to an undesirable reduction in microbiome diversity. 9 Fidaxomicin has lower recurrence rates because of its better selectivity toward C. dif f icile, but its high price limits its usage. On the other hand, vancomycin is an antibiotic of last resort against a number of deadly human pathogens, and its use must be limited in order to prevent the development of resistance. 10 In the latter respect, the emergence of bacteria that are resistant to all currently available antibiotics is a health threat of great concern. 11 It is estimated that antimicrobial resistance (AMR) will cause 700 000 deaths per year by 2050, if no immediate action is taken. 12 The financial burden of such illnesses is anticipated to be significant. Clearly, the development of new antibiotics is an urgent need. 13

Therapies from Thiopeptides

“…The advent of an efficient synthesis of micrococcins enabled a medicinal chemistry campaign that rapidly established the efficacy of 1-2 vs. CDI, even against the problematic ribotype 027, without cross-resistance to existing antibiotics. Furthermore, 1-2 were found to possess suitable pharmacokinetic properties and not harm beneficial gut biota [52]. As briefly indicated in the introduction, structure-activity relationship (SAR) work with fully synthetic materials revealed that modifications/substitutions are tolerated only on the "eastern" side chain of micrococcins.…”

Heterologous Synthesis and Characterization of Thiocillin IV

“…In our previous study, we produced micrococcin P2 (MP2), a structurally similar congener of thiocillins (Figure 1), and established the structure of MP2, which carries an aminoketone group in Thr-14. 22,23 We showed that a reasonable quantity of MP2 could be obtained using the B. cereus ATCC 14579 tcl genes. Herein, we report the biosynthetic production of thiocillin IV, identification of key enzymes responsible for O-methylation, characterization by nuclear magnetic resonance (NMR), and biological evaluations of thiocillin IV.…”

“…In our previous study, we produced micrococcin P2 (MP2), a structurally similar congener of thiocillins (Figure ), and established the structure of MP2, which carries an aminoketone group in Thr-14. , We showed that a reasonable quantity of MP2 could be obtained using the B. cereus ATCC 14579 tcl genes.…”

Identification of Micrococcin P2-Derivatives as Antibiotic Candidates against Two Gram-Positive Pathogens

“…Their elevated potency and other desirable properties qualify them as ideal starting points for the development of new antibiotics . The advent of robust synthetic methods for the production of decagram quantities of micrococcins has enabled a medicinal chemistry effort that led to the identification of preclinical candidates for impetigo (compound 6c ) and CDI (compound 6d ). , A detailed account of the medicinal chemistry and the optimization process for each indication are provided herein.…”