Magaña Angel J, Ngo David, Burgos Kenneth, Dominguez Maldonado Carolina, Abdelmaksoud Omniya, Sklenicka Jan, Tran Tung, Pasteran Fernando, Jimenez Verónica, Ramirez María S, Tolmasky Marcelo E
Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA, 92831, USA.
Instituto Nacional de Enfermedades Infecciosas, Antimicrobial Service of the National Institute of Infectious Diseases (ANLIS Dr. Carlos G. Malbran), Buenos Aires, Argentina.
Curr Microbiol. 2025 Jul 16;82(9):389. doi: 10.1007/s00284-025-04372-1.
The ongoing antibiotic resistance crisis is one of the most pressing public health challenges. Multidrug-resistant bacterial pathogens are reaching the point where some are becoming untreatable. Consequently, besides discovering novel antibiotics, alternative strategies must be explored to manage the problem. One approach is developing inhibitors that overcome resistance to antibiotics currently in use. Resistance to aminoglycosides such as amikacin is mainly due to aminoglycoside-modifying enzymes. Despite being refractory to most resistance enzymes, the semisynthetic amikacin is inactivated by aminoglycoside 6'-N-acetyltransferases type I [AAC(6')-I], of which AAC(6')-Ib is the most common in Gram-negative pathogens. The discovery that certain divalent and monovalent cations interfere with enzymatic acetylation catalyzed by AAC(6')-Ib opens possibilities for developing formulations combining antibiotics with these cations to enhance efficacy. Addition of CdCl₂ to in vitro enzymatic assays inhibited transfer of an acetyl group to the 6'-N position of amikacin, kanamycin, and tobramycin. Hence, Cd⁺ is a potential adjuvant to aminoglycosides for treating AAC(6')-Ib-mediated resistant infections. It was initially disappointing that, as with other divalent cations, CdCl₂ addition to cultures of bacteria harboring AAC(6')-Ib did not reverse resistance. However, the inhibitory action of Cd⁺ became evident when combined with the ionophore pyrithione. The complex efficiently inhibited resistance in Acinetobacter baumannii and Klebsiella pneumoniae harboring AAC(6')-Ib. Furthermore, the combination inhibited amikacin resistance in carbapenem-resistant K. pneumoniae clinical isolates. These results add another cation to the arsenal of potential aminoglycoside adjuvants, which could be developed alone or in coordination complexes with ionophores to treat multidrug-resistant infections.
持续的抗生素耐药性危机是最紧迫的公共卫生挑战之一。多重耐药细菌病原体正达到一些菌株变得无法治疗的程度。因此，除了发现新型抗生素外，还必须探索替代策略来解决这个问题。一种方法是开发能够克服对现有抗生素耐药性的抑制剂。对阿米卡星等氨基糖苷类抗生素的耐药性主要归因于氨基糖苷修饰酶。尽管半合成阿米卡星对大多数耐药酶具有抗性，但它会被I型氨基糖苷6'-N-乙酰转移酶[AAC(6')-I]灭活，其中AAC(6')-Ib在革兰氏阴性病原体中最为常见。某些二价和一价阳离子会干扰由AAC(6')-Ib催化的酶促乙酰化反应，这一发现为开发将抗生素与这些阳离子结合以提高疗效的制剂开辟了可能性。在体外酶促试验中添加CdCl₂可抑制乙酰基转移至阿米卡星、卡那霉素和妥布霉素的6'-N位。因此，Cd⁺是治疗AAC(6')-Ib介导的耐药感染的氨基糖苷类抗生素的潜在佐剂。最初令人失望的是，与其他二价阳离子一样，向携带AAC(6')-Ib的细菌培养物中添加CdCl₂并不能逆转耐药性。然而，当与离子载体吡啶硫酮结合时，Cd⁺的抑制作用变得明显。该复合物有效抑制了携带AAC(6')-Ib的鲍曼不动杆菌和肺炎克雷伯菌的耐药性。此外，该组合抑制了耐碳青霉烯类肺炎克雷伯菌临床分离株中的阿米卡星耐药性。这些结果为潜在的氨基糖苷类佐剂库增添了另一种阳离子，其可以单独开发或与离子载体形成配位复合物来治疗多重耐药感染。
