Restoring susceptibility to aminoglycosides: identifying small molecule inhibitors of enzymatic inactivation

Magaña, Angel J.; Sklenicka, Jan; Pinilla, Clemencia; Giulianotti, Marc A.; Chapagain, Prem; Santos, Radleigh; Ramírez, María Soledad; Tolmasky, Marcelo E.

doi:10.1039/d3md00226h

Cited by 5 publications

(4 citation statements)

References 155 publications

(284 reference statements)

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“…Designing or discovering adjuvants that inhibit the expression or activity of biomolecules responsible for resistance can help prevent or slow the emergence of untreatable infections [1, 6, 42]. Such infections could increase mortality rates not only from primary diseases but also by complicating medical and dental procedures [26]. Although this strategy has been extraordinarily successful in expanding the usefulness of β-lactams through the combination with β-lactamase inhibitors [43], it has not yet progressed beyond research settings for aminoglycosides [26].…”

Section: Discussionmentioning

confidence: 99%

“…Such infections could increase mortality rates not only from primary diseases but also by complicating medical and dental procedures [26]. Although this strategy has been extraordinarily successful in expanding the usefulness of β-lactams through the combination with β-lactamase inhibitors [43], it has not yet progressed beyond research settings for aminoglycosides [26]. Since the most widespread mechanism of resistance to aminoglycosides, including amikacin, involves acetylation catalyzed by the AAC(6′)- Ib enzyme [11, 16], finding inhibitors of this enzyme could allow for the treatment of numerous life-threatening infections, including those caused by carbapenem-resistant strains [21].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Recent efforts to produce inhibitors of resistance mediated by this enzyme include exploring antisense strategies to turn off the expression of the aac(6′)-Ib gene and the identification of various chemicals that interfere with the acetylation reaction [13,[17][18][19][20][21][22][23][24][25]. In particular, small molecule inhibitors have the potential to serve as inhibitors of enzyme-mediated antibiotic resistance [26][27][28]. Developing an inhibitor that can be combined with amikacin could be an option to treat infections caused by multidrug-resistant strains that can no longer be controlled by carbapenems and other antimicrobials [29].…”

Section: Introductionmentioning

confidence: 99%

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Structure-activity relationship of pyrrolidine pentamine derivatives as inhibitors of the aminoglycoside 6′-N-acetyltransferase type Ib

Sklenicka,

Tran,

Ramirez

et al. 2024

Preprint

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Resistance to amikacin and other major aminoglycosides is commonly due to enzymatic acetylation by aminoglycoside 6′-N-acetyltransferase type I enzyme, of which type Ib [AAC(6′)-Ib] is the most widespread among Gram-negative pathogens. Finding enzymatic inhibitors could be an effective way to overcome resistance and extend the useful life of amikacin. Small molecules possess multiple properties that make them attractive compounds to be developed as drugs. Mixture-based combinatorial libraries and positional scanning strategy led to the identification of a chemical scaffold, pyrrolidine pentamine, that, when substituted with the appropriate functionalities at five locations (R1 - R5), inhibits AAC(6′)-Ib-mediated inactivation of amikacin. Structure-activity relationship (SAR) studies showed that while truncations to the molecule result in loss of inhibitory activity, modifications of functionalities and stereochemistry have different effects on the inhibitory properties. In this study, we show that alterations at position R1 of the two most active compounds, 2700.001 and 2700.003, reduced inhibition levels, demonstrating the essential nature not only of the presence of an S-phenyl moiety at this location but also the distance to the scaffold. On the other hand, modifications on the R3, R4, and R5 positions have varied effects, demonstrating the potential for optimization. A correlation analysis between molecular docking values (ΔG) and the dose required for two-fold potentiation of compounds described in this and the previous studies showed a significant correlation between ΔG values and inhibitory activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structure-activity relationship of pyrrolidine pentamine derivatives as inhibitors of the aminoglycoside 6′-N-acetyltransferase type Ib

Sklenicka,

Tran,

Ramirez

et al. 2024

Preprint

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Mechanism of staphylococcal resistance to clinically relevant antibiotics

Brdová,

Ruml,

Viktorová

2024

Drug Resistance Updates

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Prevention and potential remedies for antibiotic resistance: current research and future prospects

Khan,

Sharma,

Khan

et al. 2024

Front. Microbiol.

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The increasing threat of antibiotic resistance and shrinking treatment options for infections have pushed mankind into a difficult position. The looming threat of the return of the pre-antibiotic era has caused a sense of urgency to protect and conserve the potency of antibiotic therapy. One of the perverse effects of antibiotic resistance is the dissemination of its causative agents from non-clinically important strains to clinically important strains and vice versa. The popular saying “Prevention is better than cure” is appropriate for tackling antibiotic resistance. On the one hand, new and effective antibiotics are required; on the other hand, better measures for the use of antibiotics, along with increased awareness in the general public related to antibiotic use, are essential. Awareness, especially of appropriate antibiotic use, antibiotic resistance, its dissemination, and potential threats, can help greatly in controlling the use and abuse of antibiotics, and the containment of antibiotic resistance. Antibiotic drugs’ effectiveness can be enhanced by producing novel antibiotic analogs or adding adjuvants to current antibiotics. Combinatorial therapy of antibiotics has proven successful in treating multidrug-resistant (MDR) bacterial infections. This review aims to highlight the current global situation of antibiotic resistance and discuss the methods used to monitor, prevent, inhibit, or reverse bacterial resistance mechanisms in the fight against antibiotic resistance.

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Restoring susceptibility to aminoglycosides: identifying small molecule inhibitors of enzymatic inactivation

Abstract: Growing resistance to antimicrobial medicines is a critical health problem that must be urgently addressed. Adding to the increasing number of patients that succumb to infections, there are other consequences...

Cited by 5 publications

References 155 publications

Structure-activity relationship of pyrrolidine pentamine derivatives as inhibitors of the aminoglycoside 6′-N-acetyltransferase type Ib

Structure-activity relationship of pyrrolidine pentamine derivatives as inhibitors of the aminoglycoside 6′-N-acetyltransferase type Ib

Mechanism of staphylococcal resistance to clinically relevant antibiotics

Prevention and potential remedies for antibiotic resistance: current research and future prospects

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