A mini-review: environmental and metabolic factors affecting aminoglycoside efficacy

Abstract

Following the discovery of streptomycin from Streptomyces griseus in the 1940s by Selman Waksman and colleagues, aminoglycosides were first used to treat tuberculosis and then numerous derivatives have since been used to combat a wide variety of bacterial infections. These bactericidal antibiotics were used as first-line treatments for several decades but were largely replaced by ß-lactams and fluoroquinolones in the 1980s, although widespread emergence of antibiotic-resistance has led to renewed interest in aminoglycosides. The primary site of action for aminoglycosides is the 30 S ribosomal subunit where they disrupt protein translation, which contributes to widespread cellular damage through a number of secondary effects including rapid uptake of aminoglycosides via elevated proton-motive force (PMF), membrane damage and breakdown, oxidative stress, and hyperpolarisation of the membrane. Several factors associated with aminoglycoside entry have been shown to impact upon bacterial killing, and more recent work has revealed a complex relationship between metabolic states and the efficacy of different aminoglycosides. Hence, it is imperative to consider the environmental conditions and bacterial physiology and how this can impact upon aminoglycoside entry and potency. This mini-review seeks to discuss recent advances in this area and how this might affect the future use of aminoglycosides.

Unveiling Synergistic Potency: Exploring Butyrolactone I to Enhance Gentamicin Efficacy against Methicillin-Resistant Staphylococcus aureus (MRSA) Strain USA300

“…Nevertheless, the increase in antibiotic accumulation corresponded with a decline in the MIC, proposing that elevated intracellular antibiotic levels could plausibly explain the augmented bacteriostatic efficacy. Notably, our quantitative measurements revealed considerable divergences in the distribution of antibiotics and BL-1 between inside and outside the bacterial cells, for which the majority of antibiotics failed to traverse the bacterial membrane, confirming previous studies suggested that their antibacterial efficacy hinges on aminoglycoside entry . Impressively, while BL-1 appeared to facilitate antibiotic uptake, it remained in the culture medium without penetrating into the cells.…”

“…Notably, our quantitative measurements revealed considerable divergences in the distribution of antibiotics and BL-1 between inside and outside the bacterial cells, for which the majority of antibiotics failed to traverse the bacterial membrane, confirming previous studies suggested that their antibacterial efficacy hinges on aminoglycoside entry. 14 Impressively, while BL-1 appeared to facilitate antibiotic uptake, it remained in the culture medium without penetrating into the cells. The almost negligible content of BL-1 present within the bacterial cells limits its ability to target intracellular antibiotic mechanisms, such as introducing translation errors and/or codon misreading, as well as inhibiting ribosome translocation.…”

Gausemycin Antibiotic Family Acts via Ca2+-Dependent Membrane Targeting

“…S13). Indeed early work showed aminoglycoside activity is significantly reduced under acidic pH . The MICs of aminoglycosides and glycopeptides are significantly reduced at pH > 9; in contrast, the daptomycin MICs were only slightly affected by alkaline pH (maximum 1 dilution change over a pH range from 8 to 10).…”

"The Biofilm Resistance: Many Responses but Still Many Questions"

“…Low penetration of the antimicrobial Decrease of the local concentration of the antimicrobial [15,16] Low growth rate Decrease of the efficacy of some antimicrobials (dormancy) [19][20][21] Metabolism alterations Accumulation of proteins involved in adaptation, target modifications [25,26] Oxygen gradient Decrease of the efficacy of some antimicrobials (intracellular penetration, dormancy) [33][34][35] Presence of persisters Decrease of the efficacy of some antimicrobials (dormancy) [37][38] Quorum sensing Activation of efflux pumps [43] Stress responses Cross-resistance against antimicrobials [50] A Diffusional Resistance to Inhibitors…”

“…Thus, it has been shown that oxygen penetrates the first 50 microns of biofilms [35]. These oxygen-deficient areas contribute to the ineffectiveness of some antibiotics on bacterial biofilm [36][37][38]. For example, these anaerobic microenvironments directly impact the efficacy of aminoglycosides, including intracellular transport, which requires the presence of a protomotive force [39].…”