Vancomycin Derivative Inactivates Carbapenem-Resistant Acinetobacter baumannii and Induces Autophagy

Abstract

Vancomycin is a standard drug for the treatment of multidrug-resistant Gram-positive bacterial infections. Albeit, development of resistance (VRE, VRSA) and its inefficacy against persistent infections is a demerit. It is also intrinsically inactive against Gram-negative bacteria. Herein, we report a vancomycin derivative, VanQAmC10, that addresses these challenges. VanQAmC10 was rapidly bactericidal against carbapenem-resistant A. baumannii (6 log10 CFU/mL reduction in 6 h), disrupted A. baumannii biofilms, and eradicated their stationary phase cells. In MRSA infected macrophages, the compound reduced the bacterial burden by 1.3 log10 CFU/mL while vancomycin exhibited a static effect. Further investigation indicated that the compound, unlike vancomycin, promoted the intracellular degradative mechanism, autophagy, in mammalian cells, which may have contributed to its intracellular activity. The findings of the work provide new perspectives on the field of glycopeptide antibiotics.

Vancomyxins: Vancomycin-Polymyxin Nonapeptide Conjugates That Retain Anti-Gram-Positive Activity with Enhanced Potency against Gram-Negative Strains

“…In this regard, it is noteworthy that previous reports have also described the addition of positively charged moieties to vancomycin as means of overcoming vancomycin resistance. 4 , 15 , 31 − 35 Furthermore, conjugation of vancomycin to bacteriocin nisin (1–12) has previously shown to reduce the MIC against VRE. 44 …”

“… 14 More recently, the group of Haldar reported a lipophilic cationic vancomycin analogue, VanQAmC 10 , which was shown to be bactericidal against MDR A. baumannii . 15 Another recent vancomycin derivative, developed by the groups of Wender and Cegelski, involves the introduction of an arginine-amide moiety at the vancomycin C-terminus, significantly enhancing activity against E. coli (MIC 8–16 μM) including resistant strains. 16 , 17 Notably, this arginine-vancomycin conjugate was demonstrated to successfully reduce bacterial burden >6-log fold compared to vehicle and vancomycin in a murine thigh E. coli infection model.…”

“… 6 , 8 , 10 , 18 , 19 Also of note are recent reports showing that the covalent attachment of cationic moieties to vancomycin is an effective means to resensitize clinically relevant vancomycin-resistant Gram-positive strains. 15 , 31 − 35 For these reasons, we anticipated that vancomycin-PMEN conjugates might exhibit enhanced activity toward drug-resistant Gram-positive strains as well. Here, we report the synthesis and evaluation of the vancomyxins: a new class of vancomycin-PMEN hybrid antibiotics.…”

Pursuit of next-generation glycopeptides: a journey with vancomycin

“…In this direction, our group introduced for the first time the significance of cationic–hydrophobic moieties. 32,33 We developed vancomycin conjugates bearing quaternary amino alkyl groups (with varying carbon chain length) at the C-terminal of vancomycin. Introducing alkyl groups, starting from ethyl, to octadecyl, six vancomycin analogues, having a quaternary ammonium group, separating the propyl linker and alkyl chains, were synthesized.…”

Antibiotic–cell‐penetrating peptide conjugates targeting challenging drug‐resistant and intracellular pathogenic bacteria

“…Recent examples include functionalizing vancomycin with positively charged groups and lipophilic components. For instance, the Haldar group has explored the conjugation of vancomycin to cationic lipids (Sarkar et al., 2020; Yarlagadda et al., 2014, 2015; Yarlagadda, Manjunath, et al., 2016; Yarlagadda, Samaddar, et al., 2016) and bacterial cell wall pyrophosphate binding moieties (Yarlagadda, Sarkar, et al., 2016; Yarlagadda et al., 2018). The incorporation of sulfonium‐based cationic lipophilic components to vancomycin led to enhanced interaction with the negatively charged bacterial cell membrane and increased bactericidal activity through membrane disruption (Guan et al., 2019).…”