A synthetic antibiotic class overcoming bacterial multidrug resistance

Abstract

The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern 1 . For more than five decades, the search for new antibiotics has relied heavily on the chemical modification of natural products (semisynthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semisynthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings 2 . Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, which we name iboxamycin. Iboxamycin is effective against ESKAPE pathogens including strains expressing Erm and Cfr ribosomal RNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native bacterial ribosome, as well as with the Erm-methylated ribosome, uncover the structural basis for this enhanced activity, including a displacement of the nucleotide upon antibiotic binding. Iboxamycin is orally bioavailable, safe and effective in treating both Gram-positive and Gram-negative bacterial infections in mice, attesting to the capacity for chemical synthesis to provide new antibiotics in an era of increasing resistance.

Synthetic oxepanoprolinamide iboxamycin is highly active against human pathogen Listeria monocytogenes

“…PAE is characterised by the time after antibiotic removal where no growth of the treated bacteria is observed. This prolonged action of iboxamycin has been previously noted for S. aureus and E. faecium [14]. Therefore, we next performed post-antibiotic effect experiments in L. monocytogenes, demonstrating that, indeed, iboxamycin displays pronounced PAE, suppressing the growth of the wildtype 10403S and wild-type EGD-e for 6 and 8 hours, respectively (Figure 3B,C).…”

“…Iboxamycin ( Figure 1C ) is a newly developed lincosamide with an exceptionally broad spectrum of antibacterial activity [14]. Featuring a fully synthetic, bicyclic oxepanoprolinamide aminoacyl fragment, iboxamycin improves upon previous lincosamides in its activity against both Gram-positive and Gram-negative pathogens [14].…”

“…Iboxamycin (Figure 1C) is a newly developed lincosamide with an exceptionally broad spectrum of antibacterial activity [14]. Featuring a fully synthetic, bicyclic oxepanoprolinamide aminoacyl fragment, iboxamycin improves upon previous lincosamides in its activity against both Gram-positive and Gram-negative pathogens [14]. Iboxamycin was found to be more potent than clindamycin against Gram-positive pathogens and overcomes lincosamide resistance mediated by rRNA modification by Erm and Cfr 23S rRNA methyltransferases, both of which are highly clinically important and widespread antibiotic resistance determinants [15][16][17][18].…”

“…Iboxamycin was found to be more potent than clindamycin against Gram-positive pathogens and overcomes lincosamide resistance mediated by rRNA modification by Erm and Cfr 23S rRNA methyltransferases, both of which are highly clinically important and widespread antibiotic resistance determinants [15][16][17][18]. While Cfr grants strong protection against clindamycin in clinical isolates of Staphylococcus aureus and Staphylococcus epidermidis (MIC >128 µg/mL), it confers only moderate resistance against iboxamycin (MIC of 2-8 µg/mL compared to 0.06 µg/mL for cfrstrains) [14]. Importantly, iboxamycin is also highly active against Enterococcus faecalis (MIC 0.06 µg/mL as compared to 16 µg/mL for clindamycin) -a species that is intrinsically resistant to 'classical' lincosamides as it encodes the LsaA antibiotic resistance (ARE) factor in its chromosomal genome [19], a member of the ABCF ATPase protein family that includes multiple resistance factors [20][21][22].…”

Molecular Engineering of Peptide–Drug Conjugates for Therapeutics

“…Those drugs that need to be modified may Pharmaceutics 2022, 14, 212 2 of 18 have several problems or just a key deficit that needs to be fixed, such as poor solubility in physiological environments [13], undesired toxicity [14], high dose usage [15], or poor specific targeting ability [16]. Additionally, after long-term treatments, many diseases may develop different degrees of DR or even MDR [17], including cancers [18]. Through drug modification, slight structural variations in the drugs could induce big differences in their pharmacodynamics, pharmacokinetics, and toxicity [19,20].…”