Unconventional Antibacterials and Adjuvants

Abstract

Conspectus The need for new classes of antibacterials is genuine in light of the dearth of clinical options for the treatment of bacterial infections. The prodigious discoveries of antibiotics during the 1940s to 1970s, a period wistfully referred to as the Golden Age of Antibiotics, have not kept up in the face of emergence of resistant bacteria in the past few decades. There has been a renewed interest in old drugs, the repurposing of the existing antibiotics and pairing of synergistic antibiotics or of an antibiotic with an adjuvant. Notwithstanding, discoveries of novel classes of these life-saving drugs have become increasingly difficult, calling for new paradigms. We describe, herein, three strategies from our laboratories toward discoveries of new antibacterials and adjuvants using computational and multidisciplinary experimental methods. One approach targets penicillin-binding proteins (PBPs), biosynthetic enzymes of cell-wall peptidoglycan, for discoveries of non-β-lactam inhibitors. Oxadiazoles and quinazolinones emerged as two structural classes out of these efforts. Several hundred analogs of these two classes of antibiotics have been synthesized and fully characterized in our laboratories. A second approach ventures into inhibition of allosteric regulation of cell-wall biosynthesis. The mechanistic details of allosteric regulation of PBP2a of Staphylococcus aureus, discovered in our laboratories, is outlined. The allosteric site in this protein is at 60 Å distance to the active site, whereby ligand binding at the former makes access to the latter by the substrate possible. We have documented that both quinazolinones and ceftaroline, a fifth-generation cephalosporin, bind to the allosteric site in manifestation of the antibacterial activity. Attempts at inhibition of the regulatory phosphorylation events identified three classes of antibacterial adjuvants and one class of antibacterials, the picolinamides. The chemical structures for these hits went through diversification by synthesis of hundreds of analogs. These analogs were characterized in various assays for identification of leads with adjuvant and antibacterial activities. Furthermore, we revisited the mechanism of bulgecins, a class of adjuvants discovered and abandoned in the 1980s. These compounds potentiate the activities of β-lactam antibiotics by the formation of bulges at the sites of septum formation during bacterial replication, which are points of structural weakness in the envelope. These bulges experience rupture, which leads to bacterial death. Bulgecin A inhibits the lytic transglycosylase Slt of Pseudomonas aeruginosa as a likely transition-state mimetic for its turnover of the cell-wall peptidoglycan. Once damage to cell wall is inflicted by a β-lactam antibiotic, the function of Slt is to repair the damage. When Slt is inhibited by bulgecin A, the organism cannot cope with it and would undergo rapid lysis. Bulgecin A is an effective adjuvant of β-lactam antibiotics. These discoveries of small-molecule classes of antibacterials ...

In vitro studies of the protein-interaction network of cell-wall lytic transglycosylase RlpA of Pseudomonas aeruginosa

“…A pragmatic approach in this circumstance is to prioritize members of the LT family that are demonstrated as important and/or correlate to antibiotic efficacy, and to identify their protein interactions. For P. aeruginosa , the LTs of its family that meets these criteria are the lipoproteins RlpA, MltD, and MltG; and the soluble Slt 27 , 36 , 37 .

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Polymers as advanced antibacterial and antibiofilm agents for direct and combination therapies

“…An attractive and novel strategy is to use a cationic polymer that disrupts the intrinsic antibiotic resistance mechanisms to sensitize bacteria to antibiotics to which they are naturally resistant. 106,109 There are relatively few reports on synergistic polymer-antibiotic combinations, especially combinations effective against several multi-drug resistant Gram-negative bacteria, or which potentiate multiple antibiotics. Besides potentiating the antibiotic, the combination strategy allows reduced dosing of the polymer adjuvant, which up to now has a narrower safety window than the antibiotic.…”

A multifunctional carbon dot-based nanoplatform for bioimaging and quaternary ammonium salt/photothermal synergistic antibacterial therapy

“…[4][5][6] Thus, to prevent the occurrence of bacterial diseases, huge efforts have been made regarding the development of antibacterial agents that possess super-broad-spectrum and high-efficiency antibacterial performance. [7][8][9] Recently, research on alternative strategies to combat bacterial infections has attracted considerable attention. Inspired by the advances in nanotechnology, photothermal therapy (PTT), which could use a photothermal agent (PTA) to transfer laser energy to thermal energy, 10,11 has been well developed due to its noninvasiveness, minor side effects, remote controllability, and high tissue penetration.…”

“…4–6 Thus, to prevent the occurrence of bacterial diseases, huge efforts have been made regarding the development of antibacterial agents that possess super-broad-spectrum and high-efficiency antibacterial performance. 7–9…”