Aprosamine Derivatives Active against Multidrug-Resistant Gram-Negative Bacteria

Abstract

Novel aprosamine derivatives were synthesized for the development of aminoglycoside antibiotics active against multidrug-resistant Gram-negative bacteria. The synthesis of aprosamine derivatives involved glycosylation at the C-8′ position and subsequent modification (epimerization and deoxygenation at the C-5 position and 1-N-acylation) of the 2-deoxystreptamine moiety. All 8′-βglycosylated aprosamine derivatives (3a−h) showed excellent antibacterial activity against carbapenem-resistant Enterobacteriaceae and 16S ribosomal RNA methyltransferase-producing multidrug-resistant Gram-negative bacteria compared to the clinical drug, arbekacin. The antibacterial activity of 5-epi (6a−d) and 5deoxy derivatives (8a,b and 8h) of β-glycosylated aprosamine was further enhanced. On the other hand, the derivatives (10a,b and 10h) in which the amino group at the C-1 position was acylated with (S)-4-amino-2-hydroxybutyric acid showed excellent activity (MICs 0.25−0.5 μg/mL) against resistant bacteria that produce the aminoglycoside-modifying enzyme, aminoglycoside 3-N-acetyltransferase IV, which induces high resistance against parent apramycin (MIC > 64 μg/mL). In particular, 8b and 8h showed approximately 2-to 8-fold antibacterial activity against carbapenem-resistant Enterobacteriaceae and 8-to 16-fold antibacterial activity against resistant Grampositive bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, compared to apramycin. Our results showed that aprosamine derivatives have immense potential in the development of therapeutic agents for multidrugresistant bacteria.

Synthesis and Evaluation of Novel 5‐O‐(4‐C‐Aminoalkyl‐β‐D‐ribofuranosyl) Apramycin Derivatives for the Inhibition of Gram‐Negative Pathogens Carrying the Aminoglycoside Phosphotransferase(3′)‐Ia Resistance Determinant

“…[16] With this in mind we and others have introduced the apralogs, a series of 5-O-(β-Dribofuranosyl)apramycin analogs, whose optimal members have shown improved activity over apramycin itself all while retaining its favorable toxicity profile, [17][18][19][20][21][22] a general goal that is shared by other workers in the field albeit employing a different set of modifications. [23] In the current best apralog 2 the ribose moiety is modified by the installation of an Supporting information for this article is available on the WWW under https://doi.org/10.1002/hlca.202300138 aminoethyl ether on the 3-position and by substitution of the 5-hydroxy group by an amino group. [18,24] These modifications were installed with the goals of increasing the affinity for the drug binding pocket in the decoding A site of the bacterial ribosome leading to increased activity against wild-type bacteria, [24] and to mitigate susceptibility toward inactivation by AAC(3)-IV action.…”

“…Notwithstanding the many attributes of apramycin it is inevitable that resistance mechanisms will eventually emerge against it beyond the existing but rare aminoacetyl transferase (3)IV (AAC(3)‐IV) [16] . With this in mind we and others have introduced the apralogs, a series of 5‐ O ‐(β‐ d ‐ribofuranosyl)apramycin analogs, whose optimal members have shown improved activity over apramycin itself all while retaining its favorable toxicity profile, [17–22] a general goal that is shared by other workers in the field albeit employing a different set of modifications [23] . In the current best apralog 2 the ribose moiety is modified by the installation of an aminoethyl ether on the 3‐position and by substitution of the 5‐hydroxy group by an amino group [18,24] .…”

Practical Synthesis from Streptomycin and Regioselective Partial Deprotections of (−)-(1R,2S,3R,4R,5S,6S)-1,3-Di(deamino)-1,3-diazido-2,5,6-tri-O-benzylstreptamine

“…The continued spread of multidrug resistant infectious diseases demands the equally continuous development of novel anti-infective agents with which to combat them. − The aminoglycoside antibiotics (AGAs), with their well-understood mechanisms of action and resistance, − excellent activity against Gram-negative pathogens, , and wide commercial availability, are excellent starting materials for further development and as such have undergone something of a renaissance in recent years. , These advantages are offset by nephrotoxic and ototoxic side effects , such that next-generation AGA development programs target circumvention of resistance mechanisms concomitant with the reduction of these undesirable side effects. − …”