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An organometallic structure-activity relationship study reveals the essential role of a Re(CO)₃ moiety in the activity against gram-positive pathogens including MRSA.

ABSTRACT: The worrying appearance of microbial resistance to antibiotics is a worldwide problem which needs to be tackled urgently. Microbial resistance to the common classes of antibiotics involving purely organic compounds unfortunately develops very rapidly and in most cases, resistance was detected soon after or even before release of the antibiotic to the market. Therefore, novel concepts for antibiotics must be investigated, and metal-containing compounds hold particular promise in that area. Taking a trimetallic complex (1a) which contains a ferrocenyl (Fc), a CpMn(CO)₃ (cymantrene) and a [(dpa)Re(CO)₃] residue as the lead structure, a systematic structure-activity relationship (SAR) study against various gram-positive pathogenic bacteria including methicillin-resistant Staphylococcus aureus (MRSA) strains was performed. The [(dpa)Re(CO)₃] moiety was discovered to be the essential unit for the observed antibacterial activity of 1a. The ferrocenyl and CpMn(CO)₃ units can be replaced one by one or both together by organic moieties such as a phenyl ring without loss of antibacterial activity. The most potent mono-metallic complex (9c') has an antibacterial activity comparable to the well-established organic drugs amoxicillin and norfloxacin and importantly, only moderate cytotoxicity against mammalian cells. Microbiological studies on membrane potential, membrane permeabilization, and cell wall integrity revealed that 9c' targets the bacterial membrane and disturbs cell wall integrity, but shows more efficient membrane permeabilization than the lead structure 1a.

SUBMITTER: Patra M

PROVIDER: S-EPMC5433042 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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An organometallic structure-activity relationship study reveals the essential role of a Re(CO)<sub>3</sub> moiety in the activity against gram-positive pathogens including MRSA.

Patra Malay M Wenzel Michaela M Prochnow Pascal P Pierroz Vanessa V Gasser Gilles G Bandow Julia E JE Metzler-Nolte Nils N

Chemical science 20141013 1

The worrying appearance of microbial resistance to antibiotics is a worldwide problem which needs to be tackled urgently. Microbial resistance to the common classes of antibiotics involving purely organic compounds unfortunately develops very rapidly and in most cases, resistance was detected soon after or even before release of the antibiotic to the market. Therefore, novel concepts for antibiotics must be investigated, and metal-containing compounds hold particular promise in that area. Taking ...[more]

PMID: 28553471

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Project description:The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobial-resistant pathogens requires a multifaceted effort that includes the discovery of novel therapeutic approaches. Here, we establish the capacity of the human CXC chemokines CXCL9 and CXCL10 to kill multidrug-resistant Gram-negative bacteria, including New Delhi metallo-beta-lactamase-1-producing Klebsiella pneumoniae and colistin-resistant members of the family Enterobacteriaceae that harbor the mobile colistin resistance protein MCR-1 and thus possess phosphoethanolamine-modified lipid A. Colistin-resistant K. pneumoniae isolates affected by genetic mutation of the PmrA/PmrB two-component system, a chromosomally encoded regulator of lipopolysaccharide modification, and containing 4-amino-4-deoxy-l-arabinose-modified lipid A were also found to be susceptible to chemokine-mediated antimicrobial activity. However, loss of PhoP/PhoQ autoregulatory control, caused by disruption of the gene encoding the negative regulator MgrB, limited the bactericidal effects of CXCL9 and CXCL10 in a variable, strain-specific manner. Cumulatively, these findings provide mechanistic insight into chemokine-mediated antimicrobial activity, highlight disparities amongst determinants of colistin resistance, and suggest that chemokine-mediated bactericidal effects merit additional investigation as a therapeutic avenue for treating infections caused by multidrug-resistant pathogens.IMPORTANCE As bacterial pathogens become resistant to multiple antibiotics, the infections they cause become increasingly difficult to treat. Carbapenem antibiotics provide an essential clinical barrier against multidrug-resistant bacteria; however, the dissemination of bacterial enzymes capable of inactivating carbapenems threatens the utility of these important antibiotics. Compounding this concern is the global spread of bacteria invulnerable to colistin, a polymyxin antibiotic considered to be a last line of defense against carbapenem-resistant pathogens. As the effectiveness of existing antibiotics erodes, it is critical to develop innovative antimicrobial therapies. To this end, we demonstrate that the chemokines CXCL9 and CXCL10 kill the most concerning carbapenem- and colistin-resistant pathogens. Our findings provide a unique and timely foundation for therapeutic strategies capable of countering antibiotic-resistant "superbugs."

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An organometallic structure-activity relationship study reveals the essential role of a Re(CO)₃ moiety in the activity against gram-positive pathogens including MRSA.

Publications

An organometallic structure-activity relationship study reveals the essential role of a Re(CO)<sub>3</sub> moiety in the activity against gram-positive pathogens including MRSA.

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An organometallic structure-activity relationship study reveals the essential role of a Re(CO)3 moiety in the activity against gram-positive pathogens including MRSA.

Publications

An organometallic structure-activity relationship study reveals the essential role of a Re(CO)<sub>3</sub> moiety in the activity against gram-positive pathogens including MRSA.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

An organometallic structure-activity relationship study reveals the essential role of a Re(CO)₃ moiety in the activity against gram-positive pathogens including MRSA.