Nature cover: terminator of super bacteria -- g0775

Antibiotics have been a magic drug for decades It has saved millions of lives from a once fatal infection, making complex surgery no longer difficult However, with the overuse or misuse of antibiotics in medical and agricultural fields, the problem of bacterial resistance becomes more and more serious Hans Christian gram, a Danish microbiologist, discovered in the late 19th century that bacteria can be divided into Gram-positive and Gram-negative bacteria The cell wall of Gram-positive bacteria consists of a thick and dense layer of peptidoglycan and phosphonic acid, while the cell wall of Gram-negative bacteria is a multi-layer structure, from the inside to the outside in order: thin peptidoglycan layer, lipoprotein layer / periplasmic layer, phospholipid layer and lipopolysaccharide layer This special structure leads many antibiotics (such as vancomycin) to reach their targets through the exopeptidoglycan surface of Gram-positive bacteria, but not through the outer membrane of Gram-negative bacteria For nearly half a century, no antibiotics have been approved to fight against Gram-negative bacteria Coincidentally, most of the multi drug resistant pathogens - so-called superbugs - are also gram-negative Worryingly, not only is the number of "arsenals" scarce, but many of the "weapons" we have are becoming increasingly ineffective Once these drug-resistant bacteria infect the human body, the consequences will be very dangerous or even fatal in the absence of any effective drugs Arylomycins is a natural product of macrocyclic lipopeptides, which can inhibit the type I signal peptidase (spase) of bacteria It has been proved that it has the potential to resist Gram-positive bacteria (such as Staphylococcus) In Gram-positive bacteria, the active site of spase was exposed on the cell surface, while in Gram-negative bacteria, the active site of spase was located in the periplasmic space between the plasma membrane and the outer membrane Because of its high molecular weight and lipophilicity, it is difficult to penetrate the extracellular membrane Therefore, in the past two decades, most of the scientists have focused on the development of anti - gram - positive antibiotics targeting to spase Recently, researchers of Genentech company in the United States found a new antibiotic, g0775, through structural transformation of arylomycins The antibiotic has a new membrane mechanism and has strong and broad-spectrum antibacterial activity against Gram-negative bacteria It is important that g0775 is sensitive to many pathogens with high multidrug resistance (MDR) and is not susceptible to drug resistance The research team reported their research results on the top international journal Nature under the title of "optimized arylomycins are a new class of gram-negative antiotics" The article was selected as the cover of this issue (nature, 2018, 561, 189-194) (source: nature) taking arylomycin a-c16 in Fig 1 as an example, the core skeleton of the molecular structure of arylomycin is macrocyclic tripeptide, containing N-terminal lipopeptide (purple), C-terminal carboxylic acid (green) and two phenolic hydroxyl groups (red) on the aromatic ring In order to modify it into an antibiotic with the activity against Gram-negative bacteria, the researchers explored three areas (source: nature) the researchers found that shortening the linear d-n-me-ser-d-ala-gly tripeptide in arylomycins to a single diaminobutyric acid and replacing the fatty chain with 2 - (4-tert-butylphenyl) - 4-methylpyrimidine-5-carboxylic acid could significantly improve the activity against Gram-negative bacteria (extend date Fig 6) Secondly, the researchers tried to modify the C-terminal carboxylic acid They found that 2-aminoacetonitrile group could further improve the activity against E coli and K pneumoniae, and enhance the activity against A baumannii and P aeruginosa, which are difficult to resist Finally, the researchers obtained the molecule g0775 by etherifying two phenolic hydroxyls with aminoethanol (Fig 1) Compared with arylomycina-c16, the efficacy of g0775 against eskape pathogens (E.coli, k.pneumatiae, etc.) was increased by at least 500 times In addition, g0775 was also effective against P aeruginosa and A baumannii, and significantly increased the activity of S aureus and S epidermidis (Table 1) (source: nature) the researchers also found that g0775 can bypass the existing resistance mechanism and show effective in vitro and in vivo activity against MDR Gram-negative bacteria, including the extremely resistant K pneumatiae strain CDC 0106 G0775 is in sharp contrast to the approved drugs in the fight against CDC 0106 (Table 2) (source: nature) further studies show that g0775 binds to the effector protein lepb in an unprecedented manner Aminoacetonitrile on g0775 did not bind to serine (S91) as expected, but formed an irreversible covalent bond with the nitrogen atom of lysine (k146), killing Gram-negative bacteria by inhibiting lepb In addition, the mechanism of the formation of covalent amidine bond between nitriles and k146 in g0775 was proposed: the common base (k146) involved in the hydrolysis of substrate protein acted as a nucleophilic reagent for attacking cyanogens (source: nature) finally, the researchers revealed the reason why g0775 can penetrate the outer membrane with reasonable efficiency despite its high molecular weight and high polarity: g0775 penetrates the outer membrane through a pore protein independent mechanism The mechanism by which the compound binds to the outer membrane and makes it unstable is called "self promoting uptake", and the presence of positively charged groups can promote this process Conclusion: through the structural transformation of arylomycins, researchers of Genentech company in the United States found a new antibiotic, g0775, which has a new transmembrane mechanism and strong and broad-spectrum antibacterial activity against Gram-negative bacteria.